Autonomic Nervous System - Apex Flashcards
Examples of positive feedback control in the human body include: (Select 3).:
a. generation of an AP
b. PaCO2 regulation
c. coagulation cascade
d. core temperature
e. serum glucose concentration
f. childbirth
A, F, and C
Homeostasis is a steady-state condition that comes with a price - it requires ____ to maintain the system.
energy
What does a negative feedback system dO?
Reverse a disturbance in some factors and leads to stability
What does a positive feedback system do?
Enhances or accelerates a disturbance in some factors and usually leads to instability
Any physiologic system that needs to be maintained in a normal range (set point) requires a ____.
control system
What four things must a control system be able to do:
- sense the regulated variable
- compare the input signal with an internal reference/set point
- Multiply the error signal by a proportionality coefficient (the gain) to produce an output signal
- adjust the important factor by activating an effector system
What is the most common control system for maintaining homeostasis?
A closed negative feedback loop
What are the sensors for the regulated variable - PaCO2?
central chemoreceptors
CO2 is hydrated in the ____, forming ____ which spontaneously dissociates into ___ and ___.
CSF; H2CO3; H+ and HCO3-
The PaCO2 is directly reflected by the ____, which is detected by central chemoreceptors in the _____ of the _____.
H+; retrotrapezoid nucleus of the medulla
What is the feedback controller for PaCO2?
Dorsal respiratory group (DRG)/central pattern generator (CPG)
What are the effectors for the regulated variable - PaCO2?
muscles of inspiration
An increased PaCO2 (the disturbance) results in a decreased PaCO2. What type of system is this?
A negative feedback control system
What is the sensor for the regulated variable - cervical opening?
Stretch receptors in the cervix
During L&D, sensory impulses from the stretch receptors in the cervix are sent to the _____.
hypothalamus
What is the feedback controller for the regulated variable - cervical opening?
The periventricular and supraoptic nuclei of the hypothalamus
Increased stretch impulses from the cervix received at the hypothalamus stimulate the _______ to release more _____.
posterior pituitary (neurohypophysis); oxytocin
What are the effectors for the regulated variable - cervical opening?
Oxytocin and the myometrium
Oxytocin binds to G protein-coupled receptors (Gq) on the _____, producing more ______.
myometrium; powerful uterine contractions
The fetus pushing more forcefully against the cervix and stimulating more oxytocin release is an example of which type of system?
Positive feedback cycle system
Oxytocin also stimulates _____ production by the uterine lining.
prostaglandin
Negative feedback or positive feedback??
Control of serum sodium concentration
Negative feedback
Negative feedback or positive feedback??
Enhances or accelerates a disturbance in a vital parameter
Positive feedback
Negative feedback or positive feedback??
Propagation of an AP
Positive feedback
Negative feedback or positive feedback??
Leads to stability in a vital parameter
Negative feedback
Negative feedback or positive feedback??
Leads to instability in a vital parameter
Positive feedback
Negative feedback or positive feedback??
Opposes or reverses a disturbance in a vital parameter
Negative feedback
Which method of cell signaling occurs when a cell responds to a chemical signaling molecule that the cell itself produced and secreted?
a. endocrine signaling
b. paracrine signaling
c. neurotransmitter signaling
d. autocrine signaling
D - autocrine signaling
What is the intracellular response to extracellular signals called?
Cell signaling/signal transduction
The conversion of info into a chemical change is called _____, a universal property of living cells.
signal transduction
Info arrives at cells in what 4 forms:
- Purely physical (energy)
- Chemical
- Cellular
- Extracellular matrix molecules
What are examples of purely physical/energy forms?
light, sound, heat, pressure, electricity
What are examples of chemicals?
NT, hormones, eicosanoids, drugs, toxins
What are examples of a cellular form of information arriving at cells?
Gap junctions
What are extracellular matrix molecule examples?
Collagen (think of PLT adhesion), integrins, laminin
What are the 3 main methods of intracellular communication?
- endocrine
- paracrine
- autocrine
Endocrine cell signaling = _________
a signaling molecule (i.e., a hormone) is secreted by an endocrine cell and transported through the circulation where it acts on a distant target cell
What is neuroendocrine signaling?
A specific type of endocrine signaling, where a neuron is the source of the hormone secreted into the blood
What is an example of neuroendocrine signaling?
The adrenal medulla releases epinephrine that binds to B1 receptors on the heart
What is paracrine signaling?
A chemical signaling molecule is released by one cell and acts locally to regulate the behavior of a neighboring cell
_____ cell signaling is a specific form of paracrine signaling.
Neurotransmitter
What is autocrine signaling?
A cell responds to a signaling molecule that it also produced.
NE binding to a presynaptic A2 receptor on the same nerve terminal that released NE is an example of what type of signaling?
Autocrine
What does autocoids mean?
Local hormone
Where are autocoids and paracrine hormones produced?
Locally
Autocoids and paracrine hormones are released in smaller or larger quantities than endocrine hormones?
Smaller
T/F: Autocoids and paracrine hormones are intended to act locally and are metabolized locally.
True
A chemical molecule that binds to a receptor and initiates a cellular response is called a:
a. second messenger
b. transducer
c. ligand
d. kinase
C - ligand
What does signal transduction exhibit?
specificity and sensitivity
amplification
integration
feedback
compartmentalization
desensitization
The flow of info in a signal transduction sequence follows _____ pathways.
Orderly
What are the 6 processes in signal transduction sequences?
- recognition
- transduction
- transmission
- modulation
- response
- termination
What are the 4 types of receptor-based signal transducers?
- transmembrane G protein-coupled receptors (GPCR)
- Transmembrane gated ion channels
- transmembrane enzyme-linked receptors
- Soluble nuclear (intracellular) receptors
______ is imparted by the cell-specific receptor and is mediated by the same kinds of weak, non-covalent forces the mediate enzyme-substrate interactions.
Specificity (selectivity)
Bonds ordered from weakest to strongest: ____ < _____ < ____ < ____ < _____
Van der Waals < hydrophobic < Hydrogen < ionic < covalent
When does amplification by enzyme cascade result?
When an enzyme associated with a signal receptor is activated, and in turn catalyzes the activation of many molecules of a second enzyme, which activates a third enzyme, and so on
What is integration?
The ability of a signal-transducing system to receive multiple signals and produce a unified response appropriate to the cell’s needs
Multiple components of signaling pathways are often brought together on _____ to increase their local concentration and effects.
Scaffold proteins
_____ are scaffolding proteins in addition to calcium channels.
Ryanodine receptors
When does desensitization occur?
When a signal is present continuously, desensitization of the receptor system results. (when the stimulus falls below a certain threshold, the system again becomes sensitive)
What is the general flow of info through G protein-coupled receptor signal transduction pathways?
1st messenger –> receptor –> effector –> 2nd messenger –> cellular response
The 1st step of signaling sequences is ____.
recognition of the signal by its receptor
All receptors are _____
proteins
A general term for any chemical that binds to a receptor is what?
Ligand (note - ligand immediately implies that there’s a receptor involved)
A ligand is also called what?
the first messenger
What initiates the signaling sequence?
Energy from the stimulus-receptor interaction causes a conformational change in the receptor and then initiates the signaling sequence
What is the second stage of the signaling sequence?
TRANSDUCTION of the extracellular message into an intracellular signal or 2nd messenger
The conformational change of a receptor triggers either _____ or causes the receptor to _____.
catalytic activity intrinsic to the receptor; interact with membrane or cytoplasmic enzymes
The final consequence of RECOGNITION + TRANSDUCTION is the generation of a _____ or the activation of a _____.
second messenger; catalytic cascade
What messengers are extracellular signals?
1st
What messengers are intracellular signals?
2nd
_____ are extracellular signals, ____ are intracellular signals.
1st messengers; 2nd messengers
What occurs are tranduction?
TRANSMISSION
What is transmission during the signal sequence?
The second messenger’s signal to the appropriate effector(s)
T/F: There are multiple pathways for signal transmission.
True
What are some key activities in signal transmission pathways?
- activation of kinases that add phosphates to proteins
- release or sequestration of intracellular ions
- regulation of metabolic processes
____ and _____ typically occur during transmission
Amplification and integration
What stage of the signaling sequence does amplification typically occur?
Transmission
What stage of the signaling sequence does integration typically occur?
Transmission
What occurs after transmission?
MODULATION of downstream chemicals
What are two common modulation/”on/off” events?
enzymatic phosphorylation or dephosphorylation
What occurs after modulation?
RESPONSE of the cell to the initial stimulus
What are the different types of responses?
proliferation, differentiation, cell movement, metabolism, cell behavior
What occurs after the response stage of the signal sequence?
TERMINATION of the response
How is termination often accomplished?
feedback control
What is ATP?
adenosine triphosphate
What is IP3
Inositol triphosphate
Phenylephrine is a ____ for the ____ receptor.
ligand/agonist/first messenger; alpha-1
____ is a ligand for purinergic receptors.
ATP / adenosine
What is an example of a drug that has an extracellular target?
Dabigatran
What is an example of a drug that has an adhesion molecules?
Eptifibatide
ID the 4 categories of receptor-based signal transducers.
- G protein coupled receptors
- Gated ion channels
- Enzyme-linked receptors
- Soluble nuclear receptors
What is another name for a chemical that binds to a receptor?
ligand
What family of enzymes catalyzes the addition of a phosphate group to a molecule?
Kinases
What chemical messengers are derived from arachidonic acid? (select 3)
a. prostaglandins
b. thyroxine
c. aldosterone
d. leukotrienes
e. dopamine
f. anadamide
A - prostaglandins
D - leukotrienes
F - anandamide
Most chemical signals fall into 4 categories of molecules:
1. ______
2. ______
3. ______
4. ______
- small hydrophilic molecules
- lipophilic molecules
- peptides and proteins
- others
Where are small hydrophilic molecules, peptides, and protein messengers stored?
In vesicles inside the cells that synthesize these molecules
______, _____, ____, and _____ are molecules that are not stored in vesicles.
Lipophilic molecules, purine, gas, and endocannabinoid messengers
Chemical messenger molecules bind to either _____ receptors or ____ receptors.
cell-surface or intracellular (cytoplasmic or nuclear)
What are the small hydrophilic chemical messenger classes?
Amino acids
BIogenic amines
choline esters
iodothyronines
What are 4 examples of amino acids?
- glycine
- glutamate
- GABA (y-aminobutyric acid)
- aspartate
What are 5 examples of biogenic amines?
- dopamine
- norepineprhine
- epinephrine
- serotonin (5-HT)
- histamine
What is an example of choline esters?
acetylcholine
What are 2 examples of idothyronines?
- thyroxine (T4)
- triiodothyronine (T3)
Small hydrophilic molecules are polar molecules are are ____ at physiologic pH.
ionized.
Do small hydrophilic chemical messengers readily cross plasma membranes?
No - therefore needs cell-surface receptors
____ of an amino acid precursor is a theme.
Decarboxylation
What 4 things are derived from tyrosine?
- dopamine
- NE
- Epi
- iodothyronines
T/F: GABA and glutamate can be intercoverted.
True
How are small hydrophilic chemical messengers typically released?
exocytosis (exception is T3&T4)
T3 and T4 are released through a ____
transporter
What are the 3 types of lipophilic chemical messengers?
- steroids
- eicosanoids
- miscellaneous
Vitamin D3 and retinoids are _____ messengers.
Lipophilic (nonpolar)
Prostaglandins are _____
eicosanoids
Leukotrienes are _____
eicosanoids
Thromboxanes are _____
Eicosanoids
Steroids are derived from what?
cholesterol
How do steroids circulate in the blood?
bound to a protein
T/F: Steroids can diffuse through the lipid bilayer of plasma membranes.
True
Where do steroids to receptors of target cells?
in the cytoplasm or nucleus of target cells
What are eicosanoids derived from?
polyunsaturated fatty acids w/ 18, 20, and 22 carbons
_______ is the main precursor of eicosanoids.
Arachidonic acid (20 carbons)
Eicosanoids primarily have endocrine, autocrine, or paracrine actions?
autocrine and paracrine
T/F: Unlike steroids, eicosanoids usually bind to cell surface receptors.
True
What is calcitriol, 1,25-dihydroxycholecalciferol?
Vitamin D3
What is 1,25(OH)2D3?
Vitamin D3
______ is a cholesterol derivative but it does not retain the cholesterol ring structure.
Vitamin D3
Do steroids retain the cholesterol ring strucutre?
Yes
Retinoids are derived from what?
Vitamin A
Retinoids play a role in ______.
growth and development
Peptides and protein chemical messengers are generally ____ molecules.
hydrophilic (polar)
Peptides and protein chemical messengers do or do not readily cross plasma membranes?
Do not
How do peptides and protein chemical messengers circulate in the bloodstream?
As unbound molecules
____ and _____ are nucleotides and nucleosides.
ATP and Adenosine
Adeonsine and ATP are _____.
purines
T/F: Adenosine and ATP are stored in vesicles.
False
CO and NO are or are not lipid soluble?
Are
What kind of action do CO and NO have?
paracrine
What is NO synthesized from?
amino acid L-arginine
NO and CO serve as ____ neurotransmitters.
Retrograde
Anandamide (AEA) and 2-arachidonylgycerol (2-AG) are what type of chemical messengers?
Endocannabinoids
What are endocannabinoids derived from?
arachidonic acid
What receptors do endocannabinoids bind to?
CB-1 (CNS) and CB-2 (peripheral)
Endocannabinoids are lipophilic or hydrophilic?
Lipophilic
CB-1 and CB-2 are _____ receptors.
G protein-coupled
The brain has more _____ receptors than any other type of G protein-coupled recetpor!
cannabinoid
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
Insulin - ___________
Peptide and protein molecules
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
NO - ___________
Lipophilic
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
Angiotensin II - ___________
Peptide and protein
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
Thyroxine - ___________
Hydrophilic
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
Calcitriol - ___________
Lipophilic
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
Substance P - ___________
Peptide and protein
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
GABA - ___________
Hydrophilic
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
Aldosterone - ___________
Lipophilic
Small hydrophilic molecules, lipophilic molecules, or peptide and protein molecules???
Acetylcholine - ___________
Hydrophilic
Which categories of signaling molecules are stored in vesicles in the cell that synthesized the molecules?
- small hydrophilic chemical messengers
- peptide and protein chemical messengeres
Which lipophilic chemical messengers are not derived from cholesterol?
eicosanoids, retinoids, endocannabinoids
Dopamine, Epi, NE, and the idothyroinines are derived from which amino acid?
Tyrosine
How many times does a G protein-coupled receptor span the plasma membrane?
7
What is the largest and most diverse family of receptors on the cell surface?
G protein coupled receptors (GPCR)
What ligands bind to GPCRs?
NT, hormones, vasoactive peptides, odorants, tastants, and local chemical factors
About ___ to ___ of all drugs target GPCR.
1/2 to 2/3
G proteins are molecular switches and can _____ themselves through inherent GTPase activity in the ____ subunit.
inactivate; alpha
In the GPT-loaded state, the ____ interacts with downstream effects. What may also interact with downstream effectors?
alpha subunit; beta-gamma complex
What are the 4 G protein families?
- Gs (stimulatory)
- Gi (inhibitory)
- Gq
- G12,13
What does the following represent?
Ligand –> GPCR –> Effector –> 2nd messenger –> Cell Resposne
The sequence of signal transduction through GPCR
What 3 essential components characterize signal transduction through GPCRs?
- plasma membrane receptor with 7 transmembrane helical segments
- A guanosine nucleotide-binding protein (g protein) activates the effector enzyme/path
- An effector (usually enzyme) generates 2nd messenger
GPCRs have a plasma membrane receptor with _______ transmembrane ___ segments.
7; helical
(7-TM seven-helix or serpentine receptor)
What do G proteins link?
receptor activation with a variety of downstream effects
The ___ class of G proteins are associated with 7-TM receptors.
Heterotrimeric (αβᵞ subunits)
When are G proteins turned ON?
when a ligand binds to the receptor binding site
When are G proteins turned OFF?
By the intrinsic GTPase activity in the alpha subunit
GDP is bound to the ____ subunit.
alpha
When activated, the 𝜶βᵞ complex of GPRC disassembles into a free GTP bound ___ subunit and a separate ___ complex.
𝜶; βᵞ
A _____ will stimulate (or inhibit) the production of a second messenger that will ultimately produce a change in cellular function.
G𝜶 subunit
Major effector targets of G𝜶 subunits include: (3)
- adenylate cyclases (AC)
- Phospholipase C (PLC)
- Phospholipase A2 (PLA2)
T/F: The βᵞ complex can interact with down stream effectors.
True
What are major effector targets for Gβᵞ subunits? (3)
- Gi, 0-regulated potassium channels (GIRK)
- voltage-gated calcium channels
- beta-adrenergic receptor kinase (BARK)
The alpha subunit has intrinsic GTPase activity, which catalyzes the hydrolysis of GTP to ___ and ___.
GDP and Pi
Gs stimulates _____
adenylyl cyclase
Gi inhibits ____
adenylyl cyclase
Cq11 stimulates _____
phospholipase C (PLC)
C12,13 activates ______
small G proteins
____ toxin chemically alters the Gs subunit to inhibit the intrinsic GTPase activity.
Cholera
Cholera inhibits the intrinsic GTPase activity. What occurs because of this?
continuous activation of the G protein and adenylate cylcase –> cell is swamped with cAMP –> stimulation of the export of fluid across the intestinal epithelium
____ toxin chemically alters the Gi,0 subunit
Pertussis
McCune-Albright syndrome is characterized by defects of ______.
hormonal regulation
What causes McCune-Albright syndrome?
A gain-of-function mutation of Gs that correlates w/ a massive disturbance of Gs controlled. hormone production
What causes pseudohypoparathyroidism?
A loss-of-function mutation of Gs (results in effects of PTH being suppressed –> premature puberty w/ obesity, growth retardation, and skeletal deformities)
G-alpha subunit target effector OR G-beta/gamma subunit target effector???
Adenylyl cyclase
alpha
G-alpha subunit target effector OR G-beta/gamma subunit target effector???
Phospholipase C
alpha
G-alpha subunit target effector OR G-beta/gamma subunit target effector???
Voltage-gated Ca channels
beta/gamma
G-alpha subunit target effector OR G-beta/gamma subunit target effector???
Gi,0-regulated potassium channels
beta/gamma
G-alpha subunit target effector OR G-beta/gamma subunit target effector???
Phospholipase A2
alpha
G-alpha subunit target effector OR G-beta/gamma subunit target effector???
Beta-adrenergic receptor kinase
beta/gamma
Which heterotrimeric G-protein subunit contains the intrinsic GTPase activity?
alpha
Match each enzyme with the substrate –> second messenger reaction the enzyme catalyzes.
Phospholipase A2, Adenylyl Cyclase, and Phospholipase C
ATP –> cAMP
PIP2 –> IP3 + DAG
Phospholipid –> arachidonic acid
Phospholipase A2 + Phospholipid –> arachidonic acid
Adenylyl Cyclase + ATP –> cAMP
Phospholiapse C + PIP2 –> IP3 + DAG
GPCRs target what # of downstream effectors that produce second messengers?
3
Adenylyl cyclase —> ___________
cyclic adenosine monophostate (cAMP)
PHospholipase C (PLC) —> _________
inositol triphosphate (IP3) & diacylglycerol (DAG)
Phospholipase A2 (PLA2) –> ________
Eicosanoids (20-carbon lipid mediators)
T/F: Second messenger effects are tissue specific.
True
Second messenger effects are ____ specific.
tissue
____ plays a key role int he regulation of intracellular signal transduction.
cAMP
The intracellular effects of cAMP are mediated by the enzyme _________, ____.
cAMP-dependent protein kinase, PKA
_____ is a second messenger that leads to Ca2+ release from intracellular storage sites.
IP3 (inositol-1,4,5,-triphosphate)
Many downstream signaling events mediated by Ca2+ are modulated by a Ca2+ sensing and binding protein, _____.
calmodulin (CaM)
What is the function of adenylyl cyclase?
To convert ATP to cyclic adenosine monophosphate (cAMP)
IP3 and DAG are ____ messengers
second
___ together with ___ activates PLC
Gq,11 & Ca2+
IP3 binds to what channels and where?
Ca2+ channels on the endoplasmic reticulum
What is released after IP3 binds to a channel?
Calcium
DAG in the membrane acts as a docking site for and activator of _____.
protein kinase C (PKC)
Phospholipase A2 is a ___ dependent enzyme.
Ca2+
Phospholipase A2 liberates what from the cell membrane?
Arachidonic acid
Arachidonic acid is the precursor to how many families of lipid signaling. molecules?
3
What 3 lipid signaling molecules is arachidonic acid the precursor to?
- Prostaglandins and thromboxanes (porstanoids)
- Leukotrienes
- CYP450 monooxygenases
CYP450 monoxygenases catalyze the formation of ____ and ____ from the ____ substrace.
HETEs (hydroxyeicosatetraenoic acid); EET (cis-epoxyeicosatrienoic acid); arachidonic acid
Leukotrienes are generated when ___ encounters lipoxygenase.
arachidonic acid
Prostaglandins and thromboxanes are produced by the initial action of ____ on the arachidonic acid substrate.
cyxlooxygenases
Prostanoids, leukotrienes, HETEs, and EETs are collectively called _____.
Eicosanoids
In cardiac myocytes, increased cAMP does what?
enhances contractiliy
In cardiac myocytes, increased cAMP enhances contractility (____ receptors effects).
Beta-1
_____ messenger effects are tissue-specific.
Second
In smooth muscle of airways and vessels, increased cAMP causes _______.
relaxation and dilation.
In smooth muscle of airways and vessels, increased cAMP causes relaxation and dilation (_____ receptor effects).
Beta-2
In PLTs, increased cAMP _____.
reduces PLT aggregation
In principal cells of the nephron, increased cAMP ___________________.
promotes insertion of aquaporin-2 water channels in the apical membrane
Think of ____ as the sensors of second messengers.
protein kinases
What are kinases?
Enzymes that catalyze the addition of phosphate groups (PO4 -2) to their substrate
What are common tragets for kinases?
downstream proteins
_____ catalyze the removal of phosphate groups from their substrate.
Phophatases
cAMp activates ____ to modify cellular function.
protein kinase A (PKA)
Protein Kinase A (PKA) contains 2 _____ and 2 _____.
regulatory subunits; catalytic subunits
What happens when cAMP binds to the regulatory subunits of PKA?
It causes dissociation of the catalytic subunits
What are the catalytic subunits of PKA?
Serine/threonin (Ser/Thr) kinases
What terminates the action of cAMP?
Phosphodiesterases
What terminates the action of protein kinases?
Protein phosphatases
DAG is lipophilic or hydrophilic?
Lipophilic
DAG and Ca2+ activate what?
Protein Kinase C (PKC)
What cellular functions is PKC involved in? (its a lot….)
- receptor desensitization
- modulating membrane structure events
- regulating transcription
- mediating immune responses
- regulating cell growth
- learning and memory
When is the action of DAG terminated?
When the molecule is recycled into new phospholipids
IP3 is the ___ messenger that liberates ___ from intracellular storage sites.
second; Ca2+
Ca2+ is released from ER into the ____, resulting in a dramatic increase in intracellular or extracellular Calcium?
cytoplasm; intracellular
A high _____ activates several Ca2+ dependent protein kinases and phosphatases.
cytosolic [Ca2+]
Ca2+ signals are terminated by ATP-dependent processes:
1. ______________________
2. _______________________
Ca2+ is returned into the ER
Ca2+ is pumped out of the cell
When is the action of IP3 terminated?
when the molecule is recycled into new phophoslipids
Freely available intracellular Ca2+ is a ____ messenger.
2nd
_____ is directly or indirectly involved in most cell processes, from fertilization of the ovum to cell death.
Intracellular Ca2+
Unlike other second messengers, ____ is NOT synthesized, liberated from a precursor molecule, or activated by enzymes.
Calcium (it is the increased intracellular Ca2+ that is the signal)
What are the sources of Cytoplasmic Ca2+? (6)
- voltage-gated Ca channels
- storage- operated Ca channels
- nonselective TRP ion channels
- ionotropic NT receptors (NMDA)
- IP3-controlled Ca channels (ER)
- RyR Ca selective channels
Downstream Target of Ca2+:
Voltage-gated calcium channels - _____
proteins that buffer calcium - calmodulin and calsequestrin
Downstream Target of Ca2+:
storage-operated calcium channels - _____
Calcium sensor proteins (camodulin, troponin C, synaptotagmin [presynaptic vesicle exocytosis])
Downstream Target of Ca2+:
Nonselective TRP ion channels - _____
enzymes (PLA2, PKC, NO synthases)
Downstream Target of Ca2+:
Ionotropic NT receptors (NMDA) - _____
Receptors and ion channels: IP3 receptors, RyRs, Ca-activated K and Cl channels
Removal of cytoplasmic reticulum….
voltage-gated calcium channels = _________
Na+-Ca2+ Exchanger (NCX) at the plasma membrane
Removal of cytoplasmic reticulum….
storage-operated calcium channels = _________
Ca2+-ATPase (“pump”) at the plasma membrane (PMCA)
Removal of cytoplasmic reticulum….
Nonselective TRP ion channels = _________
Ca2+-ATPase at the sarcoplasmic (muscle) or endoplasmic reticulum (SERCAs)
What Ca2+ sending and binding protein modulates may downstream events mediated by Ca2+?
Calmodulin (CaM)
When intracellular Ca2+ concentration increases, _____ Ca2+ binds to CaM inducing a major conformation change to the protein.
3-4
The active Ca2+/CaM complex has a wide range of downstream targets including:
1.
2.
3.
4.
- NO synthase
- Ca2+/CaM dependent protein kinases (ex: myosin light-chain kinase)
- adenylyl cyclase
- cAMP-specific PDE
caMP, DAG, IP3, or iCa???
Lipid second messenger
DAG
caMP, DAG, IP3, or iCa???
Generated from PIP2 and stays in the plasma membrane
DAG
caMP, DAG, IP3, or iCa???
Targets ligand activated Ca channels on the ER
IP3
caMP, DAG, IP3, or iCa???
IP3 releases it from the ER
iCa
caMP, DAG, IP3, or iCa???
Removed from the cytoplasm by pumps and transporters
iCa
caMP, DAG, IP3, or iCa???
Generated from PIP2 and diffuses in the cytoplasm
IP3
caMP, DAG, IP3, or iCa???
Activates PKA
cAMP
caMP, DAG, IP3, or iCa???
Adenylyl cyclase catalyzes production
cAMP
caMP, DAG, IP3, or iCa???
ATP is the precursor
cAMP
Which G protein alpha subunit activates adenylyl cyclase?
G-alpha S activates adenylyl cyclase
Which 2 Ca transporters are found in the plasma membrane
- sodium-calcium exchanger (NCX)
- Ca2+ ATPase (pump, PMCA)
What enzyme family catalyzes the addition of a phosphate group to a substrate?
Kinases catalyze the addition of a phosphate group to their substrates
What enzyme produces IP3 and DAG from PIP2?
PLC (phopholipase C)
The 2 types of synpases in the human body are (select 2):
a. chemical
b. thermal
c. mechanical
d. electrical
A and D
_____ play a crucial role in AP and other electrical behavior of membranes.
Ion channels
Ion channels usually have what type of pores?
gated
What helps the nervous system get the right signal to the right place in the body at the right time?
An intercellular junction called the synpase
What are the two types of synapses?
electrical and chemical
____ synapses are far more prevalent and diverse.
Chemical
____ receptors are the key proteins of signal transduction at chemical synapses.
NT
NT receptors are transmembrane proteins that are either:
1. _____
2. _____
- ion channels (ionotropic receptors)
- coupled to heterotrimeric G proteins (metabotropic receptors)
____ synapses are polarized. What does this mean?
Chemical; primarily one-way communication
What are chemical synapses comprised of?
A presynaptic terminal, synaptic cleft, and postsynaptic membrane
What is the presynaptic terminal also called?
axon terminal, synaptic bouton, or synaptic knobs
How wide is the synaptic cleft on chemical synapses?
20-40 nm wide
Ion channels are integral membrane proteins that form ________ pores through which selected ions can pass.
water-filled pores
T/F: Ion channels exhibit ion selectivity.
True
What type of channels usually have gated pores?
Ion channels
What are the 3 different types of gated ion channels?
- voltage-gated (membrane)
- ligand-gated (chemical)
- Mechanically-gated (pressure/sensory receptors)
T/F: ALL ion channels are gated.
False - not all ion channels are gated
What is an example of an ion channel that is not gated?
“leaky” potassium channels that establish resting membrane potential
Chemical synapses convert a ____ signal ➡ a ____ signal through the release of NT.
electrical; chemical
Chemical synapses communicate messages in what direction?
one direction from the presynaptic membrane to the postsynaptic membrane, across the synaptic cleft
NT act as endocrine, paracrine, or autocrine messengers?
paracrine and autocrine messengers
NT act as 1st or 2nd messenger?
1st - they bind to receptors and generate electrical or biochemical signals in postsynaptic cells
What type of synapses allow bi-directional flow?
Electrical
At electrical synapses, cells are connected by what?
gap junctions
Gap junctions consist of 2 hemichannels called _____.
connexions
What allows the myocardial cells to depolarize synchronously?
intercalated discs in the heart that contain electrical synapses
All ionotropic receptors have ____ subunits whose arrangement defines a central pore.
4-5
When does ionotropic receptor activation cease?
When the NT dissociates from the receptor or when the receptor is desensitized
Ionotropic receptors participate in fast or slow synaptic responses?
Fast
What are metabotropic receptors?
7 transmembrane-spanning receptors coupled to heterotrimeric G proteins (GPCR)
Metabotropic receptors participate in ____responses compared to inotropic receptors.
slower (seconds to minutes); compared to milliseconds or faster
AChr, adrenergic receptors, GABAbR, opioid receptors, and 5-HT1R are all _____ receptors.
metabotropic
What receptors trigger biochemical cascade?
Metabotropic - tip it sounds like metabolism or metabolite… it activates enzymes
The presynaptic terminal of chemical synapses contain what 2 important organells?
Mitochondria
Synaptic vesicles
What is mitochondria’s job in presynaptic terminals?
provides ATP, biochemical intermediates, and enzymes for the syntehsis and degradation of NT
What is synaptic vesicles job in presynaptic terminals?
concentrate, store, and deliver NT at the synapse
Membrane depolarization causes _____ channels (N-type) to open, permitting Ca2+ ions to flow into the terminal.
Ca2+
Increased intracellular Ca2+ is sensed by _____ in the docking proteins complex. This triggers the fusion of vesicles with the presynaptic membrane. This process is _____.
synaptotagmin; exocytosis
NT molecules bind to either ____ or _____ receptors on the post-synaptic membrane, leading to a post-synaptic event.
ionotropic or metabotropic
Volatile anesthetics inhibit excitatory neurotransmission (via ___ and ____ receptors).
NMDA and nicotinic ACh
Volatile anesthetics enhance inhibitor neurotransmission (via ___ and ____ receptors).
GABA and glycine
What causes hyperpolarization?
outward current of K+,
Cl= influx,
closure of Ca2+ channels
What causes depolarizatin?
net inward current of:
Na+ influx
Ca2+ influx
Reduced K+ efflux through leaky channels
Ionotropic receptor OR metabotropic receptor???
Conformational change sets in motion a biochemical cascade
Metabotropic
Ionotropic receptor OR metabotropic receptor???
Slower synaptic response
Metabotropic
Ionotropic receptor OR metabotropic receptor???
Muscarinic AChR
Metabotropic
Ionotropic receptor OR metabotropic receptor???
5-HT3R
Ionotropic
Ionotropic receptor OR metabotropic receptor???
Conformational change gates a pore
Ionotropic
Ionotropic receptor OR metabotropic receptor???
Nicotinic AChR
Ionotropic
Ionotropic receptor OR metabotropic receptor???
Opioid Receptor
Metabotropic
Ionotropic receptor OR metabotropic receptor???
Fast synaptic response
ionotropic
List 2 gases that are unconventional NT.
NO
CO
What structure connects cells at an electrical synapse?
Gap junctions (connexions form gap junctions)
Which protein in the docking complex is the calcium sensor?
Synaptotagmin
Name 3 signals that open pores in gated ion channels.
Membrane voltage (electrical), chemicals (ligands), and pressure (mechanical)
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
DOPAMINE
Biogenic Amine
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
VASOACTIVE INTESTINAL PEPTIDE (VIP)
Neuropeptide
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
OPIOIDS
Neuropeptide
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
NOREPINEPHRINE
Biogenic Amine
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
ANANDAMIDE
Nonconventional
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
GLUTAMATE
Amino Acid
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
NITRIC OXIDE
Nonconventional
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
GLYCINE
Amino Acid
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
SUBSTANCE P
Neuropeptide
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
GABA
Amino Acid
Sort each NT into the correct pile: Biogenic Amine, Neuropeptide, Amino Acid, or Nonconventional
SEROTONIN
Biogenic Amine
Where are nicotinic acetylcholine receptors NOT located?
a. autonomic ganglia
b. neuromuscular junction
c. chromaffin cells in the adrenal medulla
d. sinoatrial node
D - sinoatrial node
What is the primary NT of peripheral EFFERENT (motor) neural pathways?
Acetylcholine (ACh)
What role does Acetylcholine play in the CNS?
- the modulation of sleep
- wakefulness (in the RAS)
- learning
- memory
Where does Acetylcholine synthesis occur?
In the presynaptic nerve terminal
T/F: Cholinergic receptors can be ionotropic or metabotropic.
True
Are nicotinic ACh receptors ionotropic or metabotropic?
ionotropic
Are muscarinic ACh receptors ionotropic or metabotropic?
metabotropic
Cholinergic describes neurons or synapses that use ____ as the neurotransmitter.
Acetylcholine
Acetylcholine is the primary NT of peripheral efferent or afferent neural pathways?
EFFERENT
List all the places ACh is a NT at:
1.
2.
3.
4.
5.
- NMJ
- Autonomic ganglia
- Terminal synapses of parasympathetic postganglionic fibers
- Few sympathetic postganglionic fibers (sweat glands)
- NOn-neuronal cholinergic system (NNCS)
T/F: Only nicotinic receptors are expressed in the central neurons, not muscarinic receptors.
False - both are
What are the substrates of acetylcholine?
choline and acetyl-CoA
What is the rate-limiting factor for the availability of Acetylcholine?
The availability of its substrates (choline and acetyl-CoA)
How does glucose enter nerve terminals?
by passive transport (facilitated diffusion)
Glycolysis converts glucose to ______.
pyruvate
Where does glycolysis occur?
in the cytoplasm
An acetyl group from pyruvate is added to coenzyme A to produce _____.
acetyl-CoA
Choline is ______ transported into the presynaptic terminal.
actively
________ is the rate-limiting step in ACh synthesis.
Choline transport
What catalyzes the formation of ACh from acetyl-CoA + choline?
Choline acetyltransferase (ChAT)
Where is ACh stored?
In synaptic vesicles until release
How is ACh transported into vesciles?
By an H+-antiporter (exchanger)
_____ triggers vesicle fusion at the active zone, and ____ is released into the synaptic cleft by exocytosis.
Increased intracellular Ca2+; ACh
What hydrolyzes ACh? What is it hydorlyzed to?
Acetylcholinesterase (AChE); acetate + choline
What happens to the choline that is produced durign ACh hydrolysis?
It re-enters the nerve terminal and is reused for ACh synthesis
What is an antagonist of Ca2+ at the presynaptic nerve terminal?
Mg2+
Why does Mg2+ cause muscle weakness or potentiate NM block?
It is an antagonist of Ca2+ at the presynaptic nerve terminal
Nicotinic ACh recetpors (nAChR) are inotropic or metabotropic receptors?
Inotropic
T/F: nAChRs are nonselective anion channels.
F - nAChRs are nonselective cation channels.
Describe the structure of nAChRs.
They are pentameric complexes with 2 agonist binding sites - one at the extracellular 𝜶/ε interface of one 𝜶 subunit and the 𝜶/𝛅 interface of the other 𝜶 subunit
What is required to initiate the conformational change that opens the nAChR channels?
simultaneous binding of 2 ACh molecules to the alpha subunits
Where are NmAChRs found?
in skeletal muscle at the NMJ
Where are NnAChRs found?
in the autonomic ganglia, on the chromaffin cells of the adrenal medulla, and in the CNS
As their name implies, nAChR can be opened by the ____plant, _____.
tobacco plant, alkaloid nicotine
Muscarinic ACh receptors (mAChR) are inotropic or metabotropic receptors?
Metabotropic
Where are muscarinic AChRs found?
CNS, heart, smooth muscle, and glands of GI tract
_____ mediate most action of ACh in the CNS.
mAChR
Muscarinic AChRs are so named b/c they are activated by ____, a _____ found in a poisonous mushroom.
muscarine, a toxic alkaloid
How many types of mAChR have been identified?
5
Where are NM (nicotinic ACh) receptors found?
Skeletal muscle at NMJ
What is the signal transduction of NM (nicotinic ACh) receptors?
Opening of nonselective cation channels –> influx of Na
What is the response of activated NM (nicotinic ACh) receptors?
end-plate depolarization and skeletal muscle contraction
Where are NN (nicotinic ACh) receptors found?
Autonomic ganglia, adrenal medulla, CNS
Where are M1 (muscarinic ACh) receptors found?
autonomic ganglia
CNA
Where are M2 (muscarinic ACh) receptors found?
Heart: nodal tissue
Heart: cardiac muscle
Where are M3 (muscarinic ACh) receptors found?
Smooth muslce; GI
Where are M4 (muscarinic ACh) receptors found?
CNS
Where are M5 (muscarinic ACh) receptors found?
CNS
What muscarinic receptors are found in the heart?
M2
What muscarinic receptors are found in the GI tract?
M3
What is the signal transduction of NN (nicotinic ACh) receptors?
Opening of nonselective cation channels –> influx of sodium
What is the signal transduction of M1, M3, and M5 (muscarinic ACh) receptors?
Gq,11 –> PLC –> increased IP3 + increased DAG –> increased Ca2+ –> increased PKC
ALL ODD MUSCARINIC ARE COUPLED TO GQ
What is the signal transduction of M2 and M4 (muscarinic ACh) receptors?
βᵞ subunit of Gi –> increased K+ channel (GIRK) opening
Gi –> inhibition of AC –> decreased cAMP
ALL EVEN MUSCARINIC ARE COUPLED TO Gi
What is the response of activated NN (nicotinic ACh) receptors?
Depolarization of post-synaptic post-ganglionic neuron
Secretion of catecholamines
Arousal, attention, analgesia
What is the response of activated M1 (muscarinic ACh) receptors?
Excitatory response
Arousal, attention, analgesia
What is the response of activated M2 (muscarinic ACh) receptors?
Slowed spontaneous depolarization
DECREASES chronotropy, contracitlity, and domotropy
What is the response of activated M3 (muscarinic ACh) receptors?
Contraction
Increased salivary secretions
What is the response of activated M4 (muscarinic ACh) receptors?
Presynaptic autoreceptors –> negative feedback to supress ACh release
What is the response of activated M5 (muscarinic ACh) receptors?
Promotes dopamine release, dilation of cerebral arteries
Muscarinic AChR or Nicotinic AChR????
Binding of 2 Ach molecules for full activation
Nicotinic
Muscarinic AChR or Nicotinic AChR????
Ionotropic
Nicotinic
Muscarinic AChR or Nicotinic AChR????
NMJ
Nicotnic
Muscarinic AChR or Nicotinic AChR????
Slowed spontaneous depolarization of SA node
Muscarinic
Muscarinic AChR or Nicotinic AChR????
Coupled to heterotrimeric G protein
Muscarinic
Muscarinic AChR or Nicotinic AChR????
Secretion of catecholamines from adrenal medulla
Nicotonic
Muscarinic AChR or Nicotinic AChR????
Nonselective cation channel
Nicotinic
Muscarinic AChR or Nicotinic AChR????
Metabotropic
Muscarinic
Muscarinic AChR or Nicotinic AChR????
Presynaptic autoreceptors
muscarinic
Muscarinic AChR or Nicotinic AChR????
Airway smooth muscle
Muscarinic
The NMDA receptor has bindings sites for: (select 3)
a. gamma-aminobutyric acid
b. glutamate
c. propofol
d. ketamine
e. magnesium
f. calcium
B - glutamate
d - ketamine
e - magnesium
The amino acid NT include ____, ____, and _____.
gutamate, ᵧ-aminobutyric acid (GABA), glycine
_____ is the primary excitatory NT in the brain.
GLUTAMATE
What is the main inhibitory NT in the brain?
GABA
What is the primary inhibitor NT in teh spinal cord and lower brain stem?
GLYCINE
____ and ____ are interconvertible through Krebs cycle (aka tricarboxylic acid cycle) intermediates.
Gutamate and GABA
Are glutamate receptors inotropic or metabotropic?
they can be both
What receptors are a target for ketamine?
NMDA
What are the two ionotropic glutamate receptors?
NMDA and AMPA
What is neuronal injury initiated by excessive glutamate receptor activity called?
excitotoxicity
GABA receptors can be ionotropic and metabotropic. Which is which?
GABAa = ionotropic
GABAb = metabotropic
Which receptor is a target for Benzos, propofol, etomidate, and volatiles?
GABAa
Is the glycine receptor ionotropic or metabotropic?
ionotropic
Is glutamate excitatory or inhibitory?
excitatory
Glutamatergic synapses exist throughout the ____.
CNS
What are excitatory responses to gluatmate?
motor neuron activation, pain pathway transmission, elevated pain sensation (hyperalgesia), memory formation, cerebral neurotoxicity
Is GABA inhibitory or excitatory?
Inhibitory
Most CNS ____ and ____ express GABA receptors; therefore, GABA receptors influence many neural circuits and functions.
neurons and astrocytes
GABA neurons play a role in what?
arousal and attention; memory formation; anxiety; sleep; muscle tone
Is glycine inhibitory or excitatory?
inhibitor
What type of cells form inhibitory glycinergic synapses upon alpha motor neurons?
Renshaw
Why myst glutamate be synthesized in the brain?
B/c it canNOT cross the BBB
How is glutamate converted to GABA?
By glutamic acid decarboxylase
IN one path for glutamate synthesis, _____ produced by the Krebs cycle serves as the substrate for GABA transaminase. What is the the product of transamination?
𝜶-ketoglutarate; glutamate
How is glutamine converted into glutamate?
By glutaminase on the mitochondiral membrane
What is the rate-limiting step in glutamate synthesis?
Glutaminase activity
Where is glutamate stored until release?
synpatic vesicles
______ reuptake glutamate from the synaptic cleft via glutamate transporters.
Glial cells (glutamate is converted into glutamine by the enzyme glutamine synthetase)
What are teh 3 types of ionotropic glutamate receptors?
- N-methyl-D-aspartate (NMDA)
- 𝜶-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)
- Kainate
Where are NMDA and AMPAs both prevalently located?
hippocampus and cerebral cortex
Full activation of AMPA receptors requires waht?
binding of 2 glutamate molecules
AMPA receptors are non-selective cation channels that are highly permeable to ___ and poorly permeable to ___.
Na; Ca
AMPA are responsible for early post-synpatic membrane depolarization in response to _____ release.
glutamate
What plays a key role in AMPA desnsitization?
Phosphorylation
Full activation of NMDA receptors requires the binding of 2 ____, 2 _____ and a ______.
glutamates; glycine; depolarizing voltage change
These are safety locks on the NMDA receptor - each must be met for full activation
NMDA receptors are non-selective cation channels that are highly permeable to ___ but permeable to ___.
Ca; Na
(opposite of AMPA)
NMDAs are slower or faster gated than AMPA?
slower
NMDAs are slower-gating (Delayed) excitatory synaptic transmission.
NMDA: a _____ binding site is located within the channel, this is also the binding site for ketamine.
phencyclidine (phenylcyclohexyl piperidine, PCP; “angel dust”)
What are the 3 groups of metabotropic glutamate receptors?
- 1 coupled to Gq and activate phospholipase C
2 & 3. coupled to Gi and prevent the formation of cAMP
Metabotropic glutamate receptors are widely distributed where?
in the brain at post and pre synaptic locations and on glial cells
What is long-term potentiation?
Ca+ influx through NMDA receptors plays a key role in many Ca- dependent processes, including the consolidation of short-term memories –> long term memories
What is apoptosis?
programmed cell death
What diseases is excitotoxicity implicated as a pathologic mechanism?
Huntington’s, Alzheimer’s, ALS, stroke and trauma, hyperalgesia, epilepsy
What are the three safety locks of NMDA receptors?
voltage-dependence
2 glutamate bindings
2 glycine bindings
Why do safety locks for NMDA receptors exist?
Hyperactivation would result in flooding of neurons by Ca2+ causing cell death
What catalyzes the decarboxylation of glutamate to GABA?
Glutamic acid decarboxylase
The amount of GABA in the CNS correlates to the amount of functional ____.
Glutamic acid decarboxylase (GAD)
Where does conversion of glutamine to glutamate occur?
mitochondria
What converts glutamine to glutamate?
glutaminase
How is GABA formed and where?
By the decarboxylation of glutamate; in the cytoplasm
T/F: GAD is not present in neurons using glutamate as a NT.
True
Is GABA recylced?
Yes
How are GABAa receptors activated?
the binding of 2 GABA molecules
GABA_ receptors are pentameric ligand-gated Cl- channels.
A
GABA _ receptors are 7-transmembrane G protein-coupled receptors.
B
Activation of GABAb generates inhibitory effects in post-synaptic neurons via second messenger systes involving:
____
____
____
____
PLC
adenylyl cyclase
βᵞ unit opening of K+ channels
βᵞ closing of Ca2+ channels
How is glycine formed?
From serine (an amino acid) in an enzyme-catalyzed reaction
______ is a co-activator of the NMDA receptor.
Glycine
Mutations of the glycine receptors are involved in rare neuro dx such as ____ or ____
human startle dx or hyperekplexia
GABAa OR NMDA??????
Excitatory responses
NMDA
GABAa OR NMDA??????
Flumazenil is antagonist
GABA
GABAa OR NMDA??????
Propofol binding site
GABA
GABAa OR NMDA??????
Benzo binding site
GABA
GABAa OR NMDA??????
Inhibitory response
GABA
GABAa OR NMDA??????
Mg ions block channel at resting membrane potential
NMDA
GABAa OR NMDA??????
KEtamine binding site
NMDA
GABAa OR NMDA??????
Glycine is a co-transmitter
NMDA
What is the primary inhibitory NT in the spinal cord?
Glycine
Which NT is associated w/ excitotoxicity?
Glutamate
WHich GABA receptor is metabotropic?
b
What 2 binding sites are located in the NMDA receptor channel (pore)?
Mg2+ and Ketamine/PCP
Glutamate is converted to GABA by what type of enzymatic reaction?
Decarboxylation
Which enzymes are required to degrade epinephrine to vanillylmandelic acid? (select 2)
a. catechol-O-methyltransferase
b. L-amino acid decarboxylase
c. monomaine oxidase
d. tyrosine hydroxylase
A and C
What are the 5 biogenic amine NT?
- dopamine
- norephinephrine
- ephinephrine
- serotonin
- histamine
What are all teh biogenic amine NT derived from?
amino acids by enzymatic hydroxylation and decarboxylation
What 3 things are known as catecholamines?
dopamine, norepinephrine, epinephrine
______ is the rate limiting step in catecholamine biosynthesis.
Tyrosine hydroxylase
What 2 enzymes degrade NE and Epi?
- monoamine oxidase (MAO)
- catechol-O-methyltransferase (COMT)
What is the end-product of catecholamine metabolism?
Vanillylmandelic acid (VMA)
How is VMA eliminated?
urine
serotonin is synthesized from ____
tryptophan
What is the end product of serotonin metabolism?
5-hydroxyindoleacetic acid (5-HIAA)
How is 5-HIAA eliminated?
urine
Histamine is synthesized from _____
histidine
What physiologic responses do biogenic animes cause?
central control of cardiac function, BP, and metabolism; coordination of movement; cognitive function; regulation of appetite and feeding; sleep; behavior
Most biogenic amine NT receptors are _______ receptors. What is the exception?
metabotropic; ionotropic 5-HT3 serotonin receptor
All catecholamines are synthesized from ______.
tyrosine
Serotonin is synthesized from _______.
tryptophan
Histamine is synthesized from _______.
histidine
All biogenic amine NT are synthesized rom _______
amino acids
What 2 enzymatic reactions are common in the biosynthesis of biogenic amine NT?
Hydroxylation and decarboxylation
What occurs during hydroxylation?
An -OH group is added
What occurs during decarboxylation?
A -CO2 group is removed
If tyrosine supply is low, how can cells generate tyrosine?
From phenylalanine by hydroxylation
(tip: [maybe??? lol] the alternate name for tyrosine is hydroxyphenylalanine)
Tyrosine is hydroxylated or decarboxylated by the enzyme tyrosine hydroxylase? What is formed?
HYDROXYLATED; L-DOPA
What is the rate-limiting step in catecholamine synthesis?
Tyrosine hydroxylation to L-DOPA
During catecholamine synthesis, tyrosine hydoxylase is subject to feedback inhibition by what?
Dopamine and NE
During catecholamine synthesis, is L-DOPA hydroxylated or decarboxylated by aromatic L-amino acid decarboxylase? What is the result?
Decarboxylated; dopamine
After Dopamine is formed from L-DOPA where does it go?
It is transported into vesicles by an H+-antiporter. If the neuron is dopaminergic, the path stops here.
In nonadrenergic and adrenergic neurons or chromaffin cells, the path of catecholamine synthesis continues after Dopamine formation. In the storage vesicles, does hydroxylation or decarboxylation of the dopamine occur? What results?
Hydroxylation (by dopamine-β-hydroxylase); Norepinephrine
During catecholamine synthesis, in adrenergic cells and neurons, norepinephrine moves out of the vesicles to where? What does it encounter?
cytoplasm; phenylethanolamine-N-methyltransferase (PNMT)
PNMT catalyzes the ______ of NE to form ______.
methylation (CH3); epinephrine
Put these in order for which they are created: Norepinephrine, Dopamine, and Epinehprine
Dopamine –> Norepinephrine –> Epinephrine
What 2 enzymes metabolize catecholamines?
Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
____ is a mitochondrial outer-membrane enzyme found in most neurons and other tissues.
MAO
What two isoforms does MAO exist in?
MAO-A and MAO-B
What does MAO-A preferentially degrade?
Dopamine, Epi, serotonin
what does MAO-B degrade?
Dopamine more rapidly than serotonin or NE
_____ is a relatively nonspecific cytosolic enzyme found in endothelial cells, the heart, kidneys, liver, smooth muscle, and glial cells.
COMT
What is the end-product of catecholamien metabolism?
Vanillymandelic acid
How is pheochromocytoma diagnosis made?
biochemical determination of free catecholamine concentration and catecholamine metabolites (VMA) in urine
What is the major metabolite of dopamine? How is Dopamine metabolized?
Homovanillic acid (HVA); MAO and COMT
Does serotonin cross the BBB?
No (brain must synthesize its own)
What is the substrate for serotonin synthesis?
Dietary L-tryptophan
What is serotonin metabolized to?
5-hydroxyindoleacetic acid (5-HIAA)
How is 5-HIAA excreted? What do high levels in the urine show?
urine; consistent w/ carcinoid tumors
______ is an imidazole amine consisting of an imidazole ring and an amino group connected by 2 methylene groups.
Histamine
How is histamine synthesized in the periphery?
By mast cells and basophils
Does histamine cross the BBB?
No
The brain synthesizes its own histamine from _______.
L-histidine (an amino acid)
Histidine is _______ to form histamine
decarboxylated
What metabolizes histamine?
oxidative paths in liver
What is one major metabolite of histamine that can be measured in the urine to determine the amount of histamien that has been released systemically?
imidazole acetic acid
All catecholamine NT are derived from which amino acid?
L-tyrosine
What enxymatic reaction is present in ALL biogenic amine NT biosynthesis?
Decarboxylation
Match each adrenergic receptor with the G protein alpha subunit coupled to the receptor: alpha 2; alpha 1; beta
& Gq, Gi, Gs
Alpha-2 Receptor - Gi
Alpha-1 Receptor - Gq
Beta Receptor - Gs
How are biogenic amine NT removed from the synaptic cleft?
By reuptake into the presynaptic terminal or uptake into non-neuronal cells and organs
What are the 3 main classes adrenergic receptors can be divided into?
Alpha-1
Alpha-2
Beta
Derangements of serotonergic paths contribute to what?
Anxiety, depression, mania, schizophrenia
What serotonin receptor is the target of antagonists for PONV and Chemo-induced N/V?
5-HT3
What role do serotonergic neurons play?
sleep and wakefulness, emotions, cognition, and CV, respiratory, and intestional activitives
What role do histaminergic neurons play?
arousal and attention, memory, learning, mood
About ___% of the dopamine entering the terminal is recycled into vesicles by the H+-antiporter. The remaining ___% is destroyed by the mitochondrial enzyme MAO.
50%; 50%
Where is the largest concentration of dopaminergic neurons in the brain?
the substantia nigra
The dopaminergic neurons in the substantia nigra are crucial for what?
coordinating movements
Degeneration of Dopaminergic neurons in the substantia nigra causes _______.
Parkinson’s disease
Besides the substantia nigra, other dopaminergic neurons in the CNS are involved with ______ and ______.
motivation and reward (limbic system) and cognitive functions such as spatial learning and memory (prefrontal cortext)
How many types of dopamine receptors are there?
5
The D1-like dopamine receptors are ___ and ____. They activate what?
D1 and D5; PKA through adenylyl cyclase and cAMP, and PKC through PLC
The D2-like dopamine receptors are ___, _____, and ____. They inhibit what?
D2, D3, and D4; inhibit adenylyl cyclase and thus reduce PKA activity which ultimately leads to decreased neuronal excitability
What is implicated in the pathogensis of schizophrenia?
Overactive D2-like receptors
Where is the major concentration of noradrenergic neurons in the CNS?
Locus coeruleus in the pons
Noradrenergic neurons from the locus coeruleus reach the ___, ____, ____ and ____.
thalamus, hypothalamus, limbic system, and cerebral cortex
What the noradrenergic projections important in?
arousal, attention (Vigilance ), and feeding behaviors
2 major groups of adrenergic (epi) neurons have been identified in the CNS:
1. _________________
2. _________________
- Rostral ventrolateral medulla
- Nucleus tractus solitarius
In the peripheral nervous system, NE is released from where?
from most post-ganglionic symapthetic neurons onto the target tissues
In the peripheral nervous system, Epi is released from where?
chromaffin cells of the adrenal medulla into the circulation in response to stress
All adrenergic receptors are metabotropic or ionotropic?
Metabotropic
Adrenergic receptor classes are distinguished by their relative sensitivity to _____.
Isoproterenol (N-isopropyl-noradrenaline)
Isoproterenol activates ____ receptors, whereas ____ receptors are poorly activated by isoproterenol.
Beta; alpha
NE preferentially binds to what receptors?
A1, A2, and B1
Activation of ______ results in inhibition of NE release
presynaptic alpha-2
Epi is an agonist of what receptors?
alpha and beta
At low concentrations Epi has predominately ____ effects, while at higher concentrations, its ___ effects become more pronounced.
Beta; A1
Serotonergic neurons are clustered in several ______.
midline raphe nuclei
Rostral raphe nuclei project to the ___, ___, and ____.
thalamus, limbic system, and cortex
Caudal raphe nuclei project to the _______ and _____
spinal cord; within the brain stem
How many of the 4 main classes of serotonin receptors are metabotropic?
3
5-HT1 receptors inhibit
adneylyl cyclase
5-HT2 receptors usually stimulate ___ and _____
stimulate PLC and mobilization of Ca2+
5-HT4 receptors stimulate ______
adenylyl cylcase and pKA activation
Activation of 5-HT3 receptors leads to rapid _____
membrane depolarization
How do 5-HT3 antagonits exert their effect?
they block receptors in the area postrema as well as in the vagus nerve, which normally activates the vomiting center
Where is the highest density of histamine-containing neurons found?
in the tuberomammillary region of the hypothalamus
Gs, Gi, or Gq???????
5-HT4
Gs
Gs, Gi, or Gq???????
Alpha-2
Gi
Gs, Gi, or Gq???????
Alpha-1
Gq
Gs, Gi, or Gq???????
D1
Gs
Gs, Gi, or Gq???????
5-HT1
Gi
Gs, Gi, or Gq???????
Beta
Gs
Gs, Gi, or Gq???????
5-HT2
Gq
Gs, Gi, or Gq???????
D2
Gi
The largest concentration of dopaminergic neurons is in the brain is in what strucutre?
Substantia nigra
What cells in the adrenal medulla release Epi into the circulation?
chromaffin
Zofran targets which specific serotonin receptor?
5-HT3
What is the substrate for nitric oxide synthase?
a. L-citrulline
b. Nitric oxide
c. L-arginine
d. Guanosine triphosphate
C
What are the purinergic NT?
ATP, ADP, and adenosine
T/F: Purinergic receptors are ionotropic.
False - purinergic receptors are both ionotropic and metabotropic
ALl neuropeptides act on what receptors? and what happens?
metabotropic; they induce alterations in teh excitability of post-synaptic cells
____ is a universal intercellular messenger, acting as both an autocrine and paracrine signaling molecule.
NO
At body temp, NO is a small, ______ that easily permeates lipid membranes, “soaking” the surrounding tissue cell.
lipid-soluble gas
What does nitric oxide synthase do?
converts L-arginine to L-citrulline and NO
Many effects of NO are mediated locally by soluble guanylyl cyclase which produces ____ from GTP.
cGMP
NO plays a role in central sensitization to _____
pain
What roles do purine and pyrimidine nucleotides do?
- precursors of DNA and RNA
- components of enzymes
- energy currency
- allosteric modulators of enzymes
- second messengers
- auto-and paracrine first messengers
Purine bases are _____ and ______
adenine (A) and guanosine (G)
What are two examples of purines?
theophylline and caffeine
Pyrimidine bases are ___, ____ and ____
cytosine (C), thymidine (T), and uracil (U)
______ acid is a pyrimidine.
Barbituric
What is a nucleotide composed of?
A 5-carbon sugar(pentose), nitrogenous base, and at least 1 phosphate group
ATP, ADP and AMP and GTP, GDP, and GMP are pyrimidine or purine nucleotides?
Purine
UTP, UDP, and UMP and CTP, CDP, CMP are pyrimidine or purine nucleotides?
Pyrimidine
What is a nucleoside composed of?
A pentose and a nitrogenous base, with NO phosphate groups
(the phosphate groups differentiate a nucleoside and nucleotide)
What are the main purinergic transmitters?
ATP, ADP, and adenosine
What purinergic transmitter is frequently coreleased with other transmitters?
ATP
Adenosine is generated from ___ in the extracellular space (ex: synaptic cleft) by an enzyme, _____.
ATP; ectonucleotidase
Adenosine plays a role in the _____ state.
sleep/wake
Increased or decreased adenosine levels promote sleep?
Increased
Increased or decreased adenosine promotes wakefulness?
Decreased
Adenosine plays a crucial role in protecting tissues from damage. A strong ___ in adenosine levels. in the ECF is an emergency signal indicating an acute oxygen deficiency (CVA, angina, MI)
INCREASE
What dysrhythmia is adenosine indicated for? What does it do?
SVT; it stops the heart briefly to allow the SA node to assume the role of the dominant pacemaker
What are purinergic NT metabolized to?
5’-AMP
What are the two families of purinergic receptors?
P1 and P2
Are P1 and P2Y receptors metabotropic or ionotropic?
Metabotropic
Is P2X metabotropic or ionotropic?
Ionotropic
What role do P2X receptors play on sensory nerves?
Detect and signal tissue damage and inflammation
Some ____ receptors are found on the presynaptic membrane and serve to suppress ATP release by negative feedback through Gi paths.
P2Y
PLT aggregation is induced by ADP binding to _____ receptors.
P2Y
How does NO arise?
From the oxidation. of the guanidino group of L-arginine
What does generation of NO require?
NADPH, molecular oxygen, and is catalyzed by a family of oxygenases known as NO synthases
How many families of nitric oxide synthase are there?
3
What families of nitric oxide synthase are calcium-dependent enzymes?
NOS1 and NOS3
NO is both an ____ messenger and a ____ gas.
endogenous; cytotoxic
NO effects depend on what?
Its tissue concentration
At low concentrations, what does NO function as?
A signaling molecule and interacts w/ a cytoplasmic receptor, soluble guanylyl cyclase (sGC)
At high concentrations, NO exhibits what effects?
Signaling effects by modifying proteins by nonenzymatic S-ntirosylation
At extremely high concentrations of NO, what dominates?
the cytotoxic effects … overstimulation of NO formation plays a role in life-threatening evens such as CVA and endotoxin shock
The _____ complex activates NOS.
Ca2+-calmodulin
Activation of NOS results in the formation of ___ and ___ from L-arginine.
NO and citrulline
NO interacts with the heme moiety of ______ (sGC).
soluble guanylate cyclase
sGC activated by NO catalyzes the conversion of ___ to ____ in teh post-synaptic neuron.
GTP –> cGMP
Retrograde diffusion of NO into the pre-synatpic terminal has a ____ feedback effect.
positive
NO is a highly reactive free radical wiht a half-life of how long?
a few seconds
When are functions of NO terminated?
When NO is converted to nitrities and nitrates by oxygen and water
What roles do NO play?
sleep, controls normal feeding behavior, role in GI function
What is long-term potentiation?
An activity-dependent increase in synaptic efficacy
What is long-term depression?
A decrease in synpatic efficacy due to prolonged “weak” stimulation of a synapse
NO is synthesized and released by endothelial cells and thus has an important role in the control of ______.
vascular tone
Are GTP and ATP classified as purines or pyrimidines?
Purines
What enzyme converts ATP to adenosine in the synaptic cleft?
Ectonucleotidase
Are all neuropeptide receptors ionotropic or metabotropic?
Metabotropic
What signaling complex activates nNOS?
Ca2+/CaM (calmodulin)
An activity-dependent increase. in synaptic efficacy is called:
Long-term potentiation (LTP)
What cytosolic heme- containing enzyme is activated by NO?
Soluble guanylyl cyclase (sCG)
The receptor for insulin is a:
a. receptor guanylylcyclase
b. receptor tyrosine kinase
c. tyrosine kinase-associated receptor
d. receptor serine/threonine kinase
B
What are the 5 major categories of enzyme-linked receptors?
- receptor guanylylcyclase
- receptor tyrosine kinases
- tyrosine kinase-associted receptors
- receptor serine/threonine kinases
- receptor tyrosine phosphates
Receptor _____ convert GTP to cGMP.
guanylyl cyclases
What is the largest family of enzyme-linked receptors?
Receptor tyrosine kinases
____ and ____ are ligands to RTKs.
Insulin and growth factors
Mutations. in________ are associated with. a wide variety of cancers.
receptor tyrosine kinases (RTK)
T/F: Tyrosine kinase associated receptors do not have intrinsic enzyme activity.
True
Receptor _____ are important mediators of cell growth and differentiation.
serine-threonine kinase
Transmembrane catalytic receptors are also known as ______ receptors
enzyme-linked
What do transmembrane catalytic receptors do?
transduce an extracellular ligand-binding interaction into an intracellular effect by activating a “linked” enzymatic domain
Enzyme-Linked Receptors:
________ contain a cytosolic domain that catalyzes the formation of cGMP from GTP.
Receptor Guanylyl Cyclases
Enzyme-Linked Receptors:
______ are the largest group to transmembrane catalytic receptors.
Receptor Tyrosine Kinases
Enzyme-Linked Receptors:
________ lack inherent catalytic activity. These receptors recruit active cytosolic signaling proteins in a ligand-dependent manner.
Tyrosine Kinase Associated receptors
Enzyme-Linked Receptors:
______ have intrinisic catalytic activity and phosphorylate serine and threonine residues on target cytosolic proteins.
Receptor serin/threonine kinases
Enzyme-Linked Receptors:
_______ dephosphorylate tyrosine residues on other transmembrane receptors or on cytosolic proteins. They play important roles in cells of the immune system.
Receptor Tyrosine Pohsphates
Transmembrane catalytic receptors are ____ membrane-spanning proteins.
single
What are. theligands for enzyme-linked receptors?
Polypeptides and larger proteins
____ catalyzes teh metabolism of cGMP to 5’-GMP, terminating the actino. ofcGMP.
PDE5
____, ____, and ____ are ligands for receptor guanylyl cyclases.
ANP, BNP, and CNP
_______, a recombinant version of native natriuretic peptides, is used in the treatment of decompnesated HF.
Nesiritide
T/F: RTKs always work in pairs.
True
What tissues express higher levels of the insuline receptor?
energy-storing tissues of liver, muscle, and adipocytes
Obese people have varying degrees of _____ resistance.
leptin
Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors????
Tyrosine kinase activity is built-in to the receptor
Receptor tyrosine kinases
Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors????
Insulin receptor
Receptor tyrosine kinases
Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors????
ANP is a ligand
Receptor guanylyl cyclases
Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors????
Cell differntiation
serine-threonin kinase receptors
Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors????
TGF-β is a ligand
Serine-threonin kinase receptors
Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors????
JAK-STAT system is downstream target
Tyrosine kinase-associated receptors
Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors????
Lepitn receptor
Tyrosine kinase-associated receptors
Receptor Guanylyl Cyclases, receptor tyrosine kinases, tyrosine kinase-associated receptors, or serine-threonine kinase receptors????
GTP to cGMP
Receptor guanylyl cyclases
Which signaling molecules bind to nuclear receptors (Select 3)?
a. Ach
b. Testosterone
c. Vit D
d. Erythropoietin
e. Triiodothyronine
f. Gamma-aminobutyric acid
B, C, E
Most chemical signals bind. to receptors where?
transmembrane
________ complexes are activated transcription factors that regulate the expression of target genes in the DNA.
Ligated (ligand-bound) nuclear receptor complexes
The intracellular receptor family includes receptors for ____,____,___,___, and ____.
steroid hormones
prostaglandins
Vit d
thyroid hormones
retinoic acid
_______ are activated transcription factors that bind. in a highly specific manner. to short DNA sequences called hormone response elements.
Ligand-bound nuclear receptors
_______ increase basal metabolic rate by stimulating futile cycles of catabolism and anabolism.
Thyroid hormones
What are. the2 subfamilies of nuclear receptors?
- receptors for steroid hormones
- receptors for retinoic acid, thyroid hormone, and Vit D
Steroid hormone receptors are ______
homodimers (e.g., PR-PR for progesterone)
Receptors for retinoic acid, thyroid hormones, and Vit D form heterodimers with the _______ receptor (RXR).
retinoic acid receptor
Preferred Ligand: 17β-estradiol
Receptor/Transcription Factor: _______
Estrogen Receptor
Preferred Ligand: Progesterone
Receptor/Transcription Factor: _______
Progesterone Receptor
Preferred Ligand: Testosterone
Receptor/Transcription Factor: _______
Androgen Receptor
Preferred Ligand: Cortisol
Receptor/Transcription Factor: _______
Glucocorticoid Receptor
Preferred Ligand: Aldosterone
Receptor/Transcription Factor: _______
Mineralocorticoid receptor
Preferred Ligand: All-trans-retinoic acid
Receptor/Transcription Factor: _______
Retionic acid receptor
Preferred Ligand: 9-cis-retinoic acid
Receptor/Transcription Factor: _______
Retinoid X Receptor
Preferred Ligand: Triiodothyroinine (T3)
Receptor/Transcription Factor: _______
Thyroid hormone receptor
Preferred Ligand: 1,25-dihydroxycholecalciferol (D3)
Receptor/Transcription Factor: _______
Vitamin D Receptor
____, ____, and _____ receptors are mainly solbule cytoplasmic receptors.
Glycocorticoid, mineralocorticoid, and androgen
_____ and ____ are primarily soluble nuclear receptors.
Estrogen and progesterone
INtracellular receptors are also called ____ receptors
Nuclear
What nuclear receptors are bound. to DNA in the nucleus?
Retinoic acid, thyroid, and Vit D
_____ nuclear receptors are frequently complexed to chaperone (“heat shock”) proteins.
Cytoplasmic
T/F: Thyroid hormones have effects. onvirtually every cell in the body.
True
Free thyroid hormone, T3 and T4, enters the cell how?
Through passive diffusion and active transport
In the cell, T4 is usually converted to ____ by a ____.
T3; deiodinase
Does the thyroid receptor in the nucleus have a greater affinity for T3 or T4?
T3 (10x greater affinity)
T3 is responsible for ___% of the occupancy. of thyroid receptors in the euthyroid state.
90
Ligand-bound ____ complexes bind to thyroid response elements on DNA and act as transcription activators or repressors in a tissue-specific fashion.
TR-RXR
How do thyroid hormones increase basal metabolic rate?
By stimulating futile cycles of both catbolism and anabolism
What stage of life are thyroid hormones essential for normal human development?
Infancy
What causes congenital hypothyroidism?
Congenital deficiency of iodine and thus thyroid hormone during infancy
If hypothyroidism is recognized and corrected within _____ after birth, then development - including mental development. -can proceed almost normally.
7 -14 days
THe DNA-binding site for ligand-bound nuclear receptors. iscalled an:
Hormone response element
An unoccupied cytoplasmic intracellular receptor is frequently complexed to a/n:
Chaperone protein (heat shock protein)
An unoccupied cytoplasmic intracellular receptor is frequently complexed to a/n:
Chaperone protein (heat shock protein)
WHat syndrome is associated with congenital hypothyroidism?
Cretinism
Which statement is NOT a feature of cell death by apoptosis?
a. apoptosis is genetically programmed
b. cells shrink during apoptosis
c. plasma membranes are intact during apoptosis
d. inflammation in surrounding tissues is common during apoptosis
D
What happens during necrosis of the cell:
Cells swell or shrinks??
What happens to DNA?
What happens to plasma membranes?
What happens to cell contents?
What happens to adjacent tissues?
Cell swells
DNA condenses and dissolves
Membranes are disrupted
Contents dissolve and leak out
Adjacent tissues undergo inflammatory process
What is necrosis of the cell?
Cell death. by uncontrolled chaotic cellular events in response to cell injury
What. is apoptosis of the celll?
Genetically controlled and programmed cell death pathways
What happens during apoptosis of the cell:
Cells swell or shrinks??
What happens to DNA?
What happens to plasma membranes?
What happens to cell contents?
What happens to adjacent tissues?
-Cells shrink
-Nucleus is fragmented
-Membranes are intact
-Contents are usually intact & components are packaged into”bite-sized” apoptosomes and digested by phagocytosis
-No inflammation occurs in surrounding tissues
T/F: Apoptosis death is normal.
True
What 2 paths initiate apoptosis?
- intrinsic - mitochondrial path
- extrinsic - death receptor-initiated path
During apoptosis, the intrinsic and extrinsic paths converge on. the____ pathway.
Effector (executioner)
What drugs cause apoptosis?
Almost all chemo drugs cause apoptosis of cancer cells
Excessive levels of ____ lead to neuronal injury or neuronal death by apoptosis.
Ca2+
What are the 3 forms of cell death?
Necrosis, apoptosis, and autophagic
When does autophagic death occur?
If apoptosis is blocked or defective
Cell death: Necrosis or Apoptosis???
Process is uncontrolled
Necrosis
Cell death: Necrosis or Apoptosis???
Process is genetically programmed
Apoptosis
Cell death: Necrosis or Apoptosis???
Cell enlarges and swells
Necrosis
Cell death: Necrosis or Apoptosis???
Cell is reduced and shrinks
Apoptosis
Cell death: Necrosis or Apoptosis???
Nucleus pyknosis –> karyolysis
Necrosis
Cell death: Necrosis or Apoptosis???
Nucleus fragmentation into nucleosome sized fragments
Apoptosis
Cell death: Necrosis or Apoptosis???
Plasma membrane is disrupted
Necrosis
Cell death: Necrosis or Apoptosis???
Plasma membrane is intact; yet altered structure can occur (especially orientation of lipids)
Apoptosis
Cell death: Necrosis or Apoptosis???
Cell contents undergo enzymatic digestion and may leak out of cell
Necrosis
Cell death: Necrosis or Apoptosis???
Cell contents are intact. andmay be released in apoptotic bodies
Apoptosis
Cell death: Necrosis or Apoptosis???
Adjacent inflammation frequently occurs
Necrosis
Cell death: Necrosis or Apoptosis???
Adjacent inflammation does not occur
Apoptosis
In adults, billions of cells die each hour. in tissues such as the ___ and ____ and are replaced by new cells.
Intestine and bone marrow
The programmed destruction. ofcells during ____ is crucial to normal growth and development.
Embryogenesis
DNA damage by _____, ____, and ______ will stimulate apoptosis if the insult is mild. Larger does of the same stimuli may lead to necrosis.
radiation, cytotoxic anticancer drugs, hypoxia
What 3 neurodegenerative diseases cause accumulation. of misfolded proteins that lead to apoptosis?
Alzheimer’s, Huntington’s and Parkinson’s
What are the main biochemical features of apoptosis?
- activation. of caspases
- cell components break into fragments
- membrane alteration. and recognition by phagocytes
What 2 families of proteins are key regulators of apoptosis?
Caspases and B-cell lymphoma proteins
What are the initiator caspases?
CAS-2, -8,-9, -10
What happens after initiator caspases are activated?
Initiator caspases dimerize and undergo proteolytic cleavage from a procaspase to the active caspase
What are the effector (executioner) caspases?
CAS-3, -7
How are effector caspases activated?
By the proteolytic attack of initiator caspases
What. isthe major mechanism of apoptosis in all mammalian cells?
The mitochondiral pathway
Apoptosis (Mitochondrial Path): Damage to mitochondria by ____ or ____ result. in the opening of large pores (called ____ channels) in the mitochondrial inner membrane.
reactive oxygen species (ROS); increases. in intracellular Ca2+; Bax/Bak channels
Apoptosis (Mitochondrial Path): What resides in the cytoplasm and mitochondrial membranes that keeps Bax/Bak in check in normal healthy cells?
Bcl-2
Apoptosis (Mitochondrial Path): After the mitochondria is damaged and pores are opened, what happens?
Cytochrome C and other proteins leak through the channels; mitochondria swell and may rupture
Apoptosis (Mitochondrial Path): The _____ activates caspase-9 and commits the cell to apoptosis.
apoptosome
Apoptosis (Death Receptor-Initiated): Extracellular signals bind to. a________ receptor.
trimeric transmembrane death receptor
Apoptosis (Death Receptor-Initiated): The cytosolic portion of the death receptor has a death domain that recruits what?
Several molecules of procaspase-8
Apoptosis (Death Receptor-Initiated): The recruited procaspase-8 aggregate undergoes autoproteolytic cleavage releasing ______.
active caspase-8
Apoptosis (Executioner [death] Path):
Caspase-9 from. the____ path and caspase-8 from the ____ path converge upon executioner caspases __ and ___.
intrinsic; extrinsic; -3 and -7
What do executioner caspases do?
They are proteolytic enzymes that degrade cellular components - especially. the nucleus- into small fragments
What engulfs and processed apoptotic bodies?
Phagocytes
How quickly does phagocytosis of apoptoic cells occur?
Within minutes (so it does it w/o leaving a trace and w/o causing inflammation)
What. is signal for phagocytes to engulf the cells during apoptosis?
The phosphatidylserine phospholipid that is flipped to the outer leaflet of the membrane by caspases
Which protein keeps mitochondrial Bax/Bak pores in check. in healthy cells?
Bcl-2
Do most chemo durgs cause necrosis or apoptosis?
Apoptosis
What type. of cell digests apoptotic bodies?
Phagocytes
Intrinsic Apoptic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway???
Apoptosome activates caspase-9
Intrinsic
Intrinsic Apoptic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway???
Death pathway
Execution
Intrinsic Apoptic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway???
Caspase-8
Extrinsic
Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway???
Cell components. are packed into bite-sized apoptotic bodies
Execution
Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway???
Mitochondria initiate
Intrinsic
Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway???
Death Receptors initiate
Extrinsic
Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway???
Caspase-3 and Caspase-7
Execution
Intrinsic Apoptotic pathway OR extrinsic apoptotic pathway OR execution apoptotic pathway???
Bax/Bak channel
Intrinsic
In the presynaptic nerve terminal, opioid-activated G protein βᵞ subunits block:
a. voltage-gated Ca2+ channels
b. voltage-gated Na channels
c. voltage-gated K+ channels
d. voltage-gated Cl- channels
A - Ca2+ channels
B1 adrenoreceptor stimulation of cardiac myocytes produces positive chronotropic, dromotropic, inotropic, and lustiropic effects by ____ mediated signal transduction paths.
cAMP
Many signals. at endothelial cells lead to the production of ____ and ___
NO and vasodilation
Opioids exert _____ synaptic inhibitory responses in neurons through _____ receptor signal transduction paths.
pre and post; G protein-coupled
What plays a key role. inwater regulation at the terminal nephron?
Vasopressin (Arginine Vasopressin [AVP]) and ADH
What. is the sole enzyme for terminating cyclic nucleotide signals?
Cyclic nucleotide phosphodiesterases (PDE)
Positive inotropy = ____
contractility
Positive lusitropy = ______
relaxation
Positive chronotropy = _____
HR
Positive dromotropy = ______
conduction velocity
Stimulation of B1 G protein-coupled receptors on cardiac myocytes activates ____ and increases intracellular ___.
adenylyl cyclase; cAMP
After B1 stimulation, High levels of cAMP activate ____
protein kinase A (PKA)
The medications, ___, ___, ___ and ____ donate NO directly to vascular smooth muscle cells, leading to relaxation and vasodilations.
Nitroglycerin, sodium nitroprusside, and isosorbide dinitrate
What are the 4 families of opioid receptors?
- Mu
- Delta
- Kappa
- Nocicpetin
Opioids: In ___synpatic neurons, Gβᵞ subunits block voltage-gated Ca2+ channels.
Pre
Vasopressin plays a role in BP control at what 2 tissues?
Blood vessels and nephrons
Vasopressin binds to ____ receptors on the basolateral membrane, activating the heterotrimeric G_ protein.
g protein-coupled V2; S
PKA activation from Vasopressin does what?
Phosphorylates the water channel aquaporin 2 and activates transport. and fusion (exocytosis) of aquaporin-containing vesicles into the apical membrane
Vasopressin: Increased APQ2 in the apical membrane _____ water reabsorption.
Increases
Vasopressin binds to ___ receptors on vascular smooth muscle.
V1
What. is a phosphodiesterase?
A hydrolase that breaks a phophodiester bond
When does a phosphodiester bond happen?
When 2 hydroxyl groups of phosphoric acid (H3PO4) react w/ 2 hydroxyl groups attached to carbons to form 2 ester bonds
______ form the backbone of DNA and RNA.
Phosphodiester bonds
How many families of phosphodiesterases are there?
11
PDE__ is nonselective for cAMP and cGMP, but binds to cAMP w/ 10x the affinity of cGMP binding.
3
Where is PDE3 found?
Heart, vascular and placental smooth muscle, and tissues important in energy homeostasis (liver, pancreatic beta cells, adipocytes)
Name 2 selective PDE3 inhibitors.
Milrinone and (in)amrinone
T/F: 2nd messengers are tissue specific.
True
PDE3 inhibitors ___ cAMP levels
increase
What are the outcomes of PDE3 inhibitors?
Positive chronotropy, dromotropy, inotropy, and lustiropy & vasodilation
What is Milrinone used for?
PHTN, cerebral vasospasm after aneurysmal subarachnoid hemorrhage, neonatal septic shock
How is milrinone eliminated?
REnal excretion
PDE__ is cGMP selective.
PDE5
Where is PDE5 found? Where. isthe highest concentration?
tissues throughout the body;
Corpus cavernosus (penis & clitoris), vascular smooth muscle, and PLT
Name 3 PDE5 inhibitors.
Sildenafil, Vardenafil, Tadalafil
What are PDE5 inhibitors used for?
Erectile dysfunction, PHTN, high-altitude sickness, memory dysfunction
How are PDE5 inhibitors metabolzied?
by CYP450 in liver
PDE__ is cAMP selective.
4
What does PDE4 do?
MOdulates B2-adrenergic responses in pulmonary smooth muscle
Name 1 PDE4 med. What is it used for?
Roflumilast; COPD
What are weak, nonselective inhibitors of PDE?
Methylxanthines (caffeine and theopylline)
PDE3, PDE4, or PDE5???
Nonselective for cAMP and cGMP
3
PDE3, PDE4, or PDE5???
cAMP selective
4
PDE3, PDE4, or PDE5???
Milrinone is. aninhibitor
3
PDE3, PDE4, or PDE5???
Inhibitors. are metabolized by CYP450 3A4
5
PDE3, PDE4, or PDE5???
Sildenafil is an inhibitor
5
PDE3, PDE4, or PDE5???
cGMP selective
5
PDE3, PDE4, or PDE5???
Inhibitors are called inodilators
3
PDE3, PDE4, or PDE5???
Roflumilast is an inhbiitor
4
PDE3, PDE4, or PDE5???
Modulates B2 responses in pulmonary smooth muscle
4
Inhibition. of SRCA2 is relieved. by phosphorylation of?
Phospholamban
Endothelial nitric oxide synthase (eNOS) is activated by?
Ca2+CaM complex
Water reabsorption in principal cells of the collecting duct is increased by the insertion of what protein into the apical membrane?
Aquaporin 2 (APQ2)
What are the synonyms for Vasopressin?
- arginine vasopressin (AVP)
- antidiuretic hormone (ADH)
Which is NOT a division of the ANS?
A. sympathetic
B. somatic
C. parasympathetic
D. enteric
B
The visceral nervous system is synonymous with. the ____ nervous system.
autonomic
What. arethe 3 divisions of the ANS?
sympathetic nervous system, parasympathetic nervous system, and enteric nervous system
Where does the ANS proide neural control to?Where does it not?
All parts of the body except skeletal muscle
____ nervous system is a major player. in homeostasis.
Autonomic
Central nervous system = ____ + _____
brain + spinal cord
Peripheral nervous system = ___ + ____
12 pairs of CN + 31 pairs. of spinal nerves
Voluntary control of skeletal muscle is the _____
somatic
Involuntary control of glands and smooth muscle is the ____
autonomic
Why is CN2 part of the CNS structuarlly?
It is covered in 3 meningeal layers
What do somatic nervers innervate?
Musculoskeletal strucutres and sensory organs of the skin
What do autonomic nerves innervate?
Smooth muscle, cardiac muscle, and glands
____ results in the absence of autonomic tone to a particular organ.
Denervation
Which anatomic part of the nervous system is surrounded and covered by the meninges?
CNS
Which type of muscle does NOT receive ANS signals?
Skeletal muscle
Sympathetic or Parasympathetic???
Miosis
Parasympathetic
Sympathetic or Parasympathetic???
Mass Discharge
Sympathetic
Sympathetic or Parasympathetic???
Artery tone
Sympathetic
Sympathetic or Parasympathetic???
Accommodation. inthe eye
Parasympathetic
What are the 3 forms extracellular signals take?
- chemical
- electrical
- mechanical
What are thh 3 major categories of membrane-bound receptors?
- Ion channels
- G protein-coupled receptors
- Enzyme-linked receptors
Where are intracellular receptors located?
The cytoplasm or nucleoplasm
____ is. theprocess by whihc a cell converts this extracellular signal into an intracellular response.
Signal transduction
T/F: An ion channel is open or closed.
True
What. are the 2 ways in which a GPCR can work?
- opening or closing an ion channel
- activating or inhibiting enzyme inside the cell
When an enzyme-linked receptor is at rest, the catalytic domain is inactive. oractive?
Inactive
The insulin receptor in skeletal muscle being linked to an enzyme called tyrosine kinase is an example. of ______ receptors.
enzyme-linked
Steroids bind to receptors in the ____. Ths is an example of ____ receptors.
cytoplasm; intracellular
Thyroid hormones bind to receptors in the ____. Ths is an example of ____ receptors.
nucleus; intracellular
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
B1 Receptor
GPCR
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Alpha or beta-gamma subunit opens or closes an ion channel
GPCR
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Thyroid hormone receptor
Intracellular
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Signal diffuses through membrane
Intracellular
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Ligand binding to receptor activates catalytic domain
Enzyme
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Substance flows along concentration gradient
Ion channel
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Located in cytoplasm of nucleoplasm
Intracellular
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Voltage gated potassium channel
Ion channel
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Insulin receptor
Enzyme linked
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Channel opens or closes
ion channels
Ion channel, GPCR, Enzyme-linked, or Intracellular?????
Activates or inhibits an intracellular enzyme
GPCR
Which is NOT a second messenger?
a. calcium
b. cyclic adenosine monophosphate
c. inositol triphosphate
d. glutamate
D
Name the signaling sequence of GPCRs:
1st messenger (ligand) –> GPCR –> Effector –> 2nd messenger –> cellular response
What 3 subunits are. inteh G protein component of GPCR?
alpha, beta, gamma
What activates. theG protein?
The ligand-receptor interaction
What is the function of an effector?
To activate or inhibit second messengers
The intracellular response to second messengers is ___ specific.
Tissue
Name 5 2nd messengers.
- cAMP
- cGMP
- Inositol triphosphate (IP3)
- Diacylgylcerol (DAG)
- Calcium Ion (CA2+)
An example. of an endogenous ligand is a ____ or _____.
NT or hormone
A _____ binds to the GPCR.
Ligand
Where does the receptor portion of the GPRC lie?
Outside the cell membrane
Where does the G protein reside?
Inside the cell membrane
What types of G-proteins turn on effectors?
Gs and Gq (these are stimulatory)
What types of G-proteins turn off an effectors?
Gi
What activates. a G-protein?
The ligand-receptor interaction
What happens when the G-protein is activated?
The alpha subunit dissociates from the beta and gamma subunits
When does the alpha subunit rejoin the beta and gamma subunits of a G-protein?
When the ligand unbinds from the receptor
What is the purpose of the effector of GPCR?
To produce or activate the 2nd messenger
Enzymatic effectors (that activate/produce the 2nd messenger) include _____ and _______.
adenylate cyclase and phospholipase C
Ion channel effectors (that activate the 2nd messenger) include _____ and ________, at the _____.
GABA-a receptors and M2 receptors. at the SA node
What process allows a single molecule to initiate a process that activates a large number of physiologic changes - each step progressively increasing the magnitude of response? What system allows for this process?
Signal amplification; Second messenger system
The second messenger modulates a network of enzymatic activity, including ____ and ____.
phosphatases and protein kinases
Which component of the GPCR signaling sequence allows for amplification?
second messenger
Stimulation of which receptors increases phospholipase C activity? (select 2)
a. Alpha 1
b. vasopressin 1
c. beta-1
d. muscarinic 2
A and B
Gs alpha subunits stimulate what?
adenylate cyclase
What does Gs alpha stimulation promote?
Increased cAMP levels
Gi alpha subunits inhibit what?
Adenylate cyclase
What does Gi inhibition result in?
decreased cAMP levels
Gq alpha subunits activate what? And what does this cause?
Phospholipase C; increased IP3, DAG, and Ca2+
Gq –> Increased ________ effector
Phospholipase C
Gi –> Decreased ________ effector
Adenylate Cyclase
Gs –> Increased ________ effector
Adenylate Cyclase
Gs - second messenger??
increased cAMP
Gi - second messenger??
Decreased cAMP
Gq - second messenger??
Increased IP3, DAG, Ca2+
What is the signal transduction of Alpha 1? (Gq, Gi, or Gs??)
Gq
What is the signal transduction of Alpha 2? (Gq, Gi, or Gs??)
Gi
What is the signal transduction of Beta 1? (Gq, Gi, or Gs??)
Gs
What is the signal transduction of Beta 2? (Gq, Gi, or Gs??)
Gs
What is the signal transduction of Beta 3? (Gq, Gi, or Gs??)
Gs
What is the signal transduction of Nicotinic Receptors?
Ion channels
What is the signal transduction of M1? (Gq, Gi, or Gs??)
Gq (1,3,5 are all Gq)
What is the signal transduction of M3? (Gq, Gi, or Gs??)
Gq (1,3,5 are all Gq)
What is the signal transduction of M5? (Gq, Gi, or Gs??)
Gq (1,3,5 are all Gq)
What is the signal transduction of M2? (Gq, Gi, or Gs??)
Gi (2, 4 are Gi)
What is the signal transduction of M4? (Gq, Gi, or Gs??)
Gi (2 & 4 are Gi)
What is the signal transduction of Dopamine 1 (postsynaptic)? (Gq, Gi, or Gs??)
Gs
What is the signal transduction of Dopamine 2 (presynaptic)? (Gq, Gi, or Gs??)
Gi
What is the signal transduction of Vasopressin 1 (vasculature)? (Gq, Gi, or Gs??)
Gq
What is the signal transduction of Vasopressin 2 (renal tubules)? (Gq, Gi, or Gs??)
Gs
What is the signal transduction of Histamine 1? (Gq, Gi, or Gs??)
Gq
What is the signal transduction of Histamine 2? (Gq, Gi, or Gs??)
Gs
Match each receptor with its physiologic action?
A2 M3 B2 B1
Increased automaticity
Coronary vasoconstriction
Skeletal muscle vasodilation
Bronchoconstriction
Increased automaticity - B1
Coronary vasoconstriction - A2
Skeletal muscle vasodilation - B2
Bronchoconstriction - M3
What does parasympathetic nervous stimulation of M2 receptors cause?
Decreased rate, contraction, and conduction velocity
______ nervous system of B1 receptors. atthe heart causes increased rate, contraction, and conduction velocity.
Sympathetic
Do arteries and veins receive PNS input?
No
Arteries and veins receive no PNS input, in general. What are the excpetions?
Coronary vessels (vasodilation) and cerebral vessels (receptor-specific vasodilation or vasoconstriction)
SNS stimulation of most arterial vessels causes ______ via what receptors?
vasoconstriction; A1
SNS activation of ___ receptors on veins produces venoconstriction.
A2
SNS stimulation of B2 receptors on most arterial vessels produces what?
vasodilation
What is the PNS effect upon airway smooth muscle and through what receptor?
Contraction of airway smooth muscle; M3
SNS activity produces ____ of airway smooth muscle
relaxation (b2 receptors)
SNS:
Effector - Heart
Receptor - ______
B1
SNS:
Effector - Lungs
Receptor - ______
B2
SNS:
Effector - GI Tract
Receptor - ______
A1
SNS:
Effector - Glands
Receptor - ______
A1
SNS:
Effector - Urinary Tract
Receptor - ______
A1, B2
SNS:
Effector - Skin
Receptor - ______
A1
SNS:
Effector - Skeletal Muscle
Receptor - ______
B2
SNS:
Effector - Pupils
Receptor - ______
A1
SNS:
Effector - Heart
Receptor - B1
Effect - ________
Positive inotropic, chronotropic, and dromotropic effect
SNS:
Effector - Lungs
Receptor - B2
Effect - ________
Bronchodilation
SNS:
Effector - GI Tract
Receptor - A1
Effect - ________
Vasoconstriction; Sphincter contraction
SNS:
Effector - Glands
Receptor - A1
Effect - ________
Increased sweating
Decreased pancreatic activity
SNS:
Effector - Urinary Tract
Receptor - A1, B2
Effect - ________
Bladder sphincter contraction
Increased renin secretion
SNS:
Effector - Skin
Receptor - A1
Effect - ________
Vasoconstriction
SNS:
Effector - Skeletal Muscle
Receptor - B2
Effect - ________
Vasodilation
SNS:
Effector - Pupils
Receptor - A1
Effect - ________
Dilation
PNS:
Effector - Heart
Receptor - ______
M2
PNS:
Effector - Lungs
Receptor - ______
M3
PNS:
Effector - GI Tract
Receptor - ______
M3
PNS:
Effector - Glands
Receptor - ______
M1, M3
PNS:
Effector - Urinary Tract
Receptor - ______
M3
PNS:
Effector - Pupils
Receptor - ______
M3
PNS:
Effector - Heart
Receptor - M2
Effect - ______
Negative inotropic, chronotropic, and dromotropic effect
PNS:
Effector - Lungs
Receptor - M3
Effect - ______
Bronchconstriction
Increased galnd secretion
PNS:
Effector - GI Tract
Receptor - M3
Effect - ______
Increased motility
Sphincter relaxation
Increased gland secretion
PNS:
Effector - Glands
Receptor - M1, M3
Effect - ______
Increased salivation
Increased lacrimation
Increased pancreatic activity
PNS:
Effector - Urinary Tract
Receptor - M3
Effect - ______
Bladder sphincter relaxation
PNS:
Effector - Pupils
Receptor - M3
Effect - ______
Constriction
