Chapter 5 Cell Signaling in Physiology Flashcards
What is the importantance of Receptor Physiology?
Essential to both the nervous system and endocrine system functions
How do the nervous system and endocrine system functions work together?
Work together to maintain homeostasis
What is important about the nervous system?
It is fast, specific, quickly ends, uses neurotransmitters
What is important about the endocrine system?
Slow, longer lasting, less specific, uses hormones
What do both the nervous system and endocrine system use?
Both use chemical messengers (ligands) that bind receptors on target cells
What is pharmacology?
Study of chemical messengers acting upon receptors of cells/tissues
What does a receptor do?
Detect stimulu
What are examples of neurotransmitters?
ACh (acetylcholine), NE (norepinephrine), DA (dopamine)
What are neurotransmitters?
Chemical released by a neuron that acts primarily on postsynaptic cell
Ex. ACh, NE, DA, etc
What are intercellular signaling agents?
Or ligands
Neurotransmitters
Hormones
Neuropeptides
What are the types of hormones?
Hormonal, paracrine, autocrine, juxtacrine
What is Juxtacrine?
Cell-cell or cell-ECM signaling in which there is contact between structures involved
Contact dependent signaling
What is paracrine?
Signals diffuse to and affect nearby cells
What is autocrine?
Term for hormones that act on same cells that secrete them
What is a neuropeptide?
2 or more amino acids joined by peptide bond(s)
Differ from other chemical messenger groups -synthesis method -location within neurons
Cleaved from larger, biologically inactive molecules
Synthesis occurs within soma & transported to synaptic terminals
Potent at very small amounts, neuromodulation
What are differences between neuropeptides and neurotransmitters?
NP: short chains of AA, serve as NT, slow acting, slow response, prolonged action, act on number of receptor proteins, alter gene expression
NT: endogenous chemical enable neurotransmission, fast acting, quick response, short term response, act on specific receptor, do not alter gene expression
How do neuropeptides differ form other chemical messenger groups?
Synthesis method
Location within neurons
What are large groups of neuropeptides?
Endogenous opiods
Opiates
What are endogenous opioids?
Beta endorphin
Enkephalins
Modulate pain awareness, eating, mood, drinking
What are Opiates?
Morphine, Codeine
Powerful opiates -> analgesics (pain reliever/pain killer)
What is the difference between an analgesic and an anesthetic?
Analgesic: decreases pain awareness but still conscious
Anesthetic; alters consciousness
What is a neuromodulator?
Variety of actions depending on specific neuronal interaction
Modulating neuronal activity
Neuromodulator alters postsynaptic cell causing
increase or decrease or inhibit synaptic activity
Neuromodulator alters presynaptic cell causing
impacting release, uptake, synthesis or metabolism of a NT
What are enkephalins?
Neuromodulator family
Small peptides
Inhibit (-) spinal interneurons from transmitting pain signals
What is nitric oxide (NO) ?
Simple neuromodulator
Lightweight gas, released by postsynaptic brain neurons involved in learning & memory
Stimulates presynaptic neuron to release more NT
What are characteristics about the types of receptors?
Most ligands are water-soluble and bind to external surface PM receptors
A minority of messengers are lipid-soluble
What do water-soluble receptors do?
Bind to external surface of plasma membrane receptors
What do messenger receptors do?
Steroids
Lipid-soluble and bind to intracellular receptors
What are plasma membrane receptors?
Usually a transmembrane protein
Ligands (peptides, protein hormones)
Water soluble
Hydrophilic (water loving)
Lipophobic (lipid fearing)
Usually activate rapid, short-lived response
What are ligands in plasma membrane receptors?
Peptides
Protein hormones
What are intracellular receptors?
Able to diffuse through lipid bilayer
Ex. Steroids, TH
Bind within cell to receptors in cytosol or nucleus
Lipid soluble
Hydrophobic (water fearing)
Lipophilic (lipid loving)
Usually alters gene expression
Require a transport protein
Often slower response but longer lasting compared to plasma membrane receptors
What are examples of intracellular receptors?
Steroids
Thyroid hormone
What is a hydrophobic signal?
Requires a carrier protein while in the plasma , but at the target cell the signal moves easily through the membrane and binds to its receptor, found either in the cytosol or in the nucleus
How do intracellular receptors alter gene expression?
Can act upon greater than or equal to 1 or more genes , can increase or decrease gene expression or both
What are the 4 major types of interactions between receptors and ligands?
Specificity
Affinity - also electric
Saturation
Competition
What is receptor - ligand specificity?
Ability of a receptor to bind only one type or a limited number of structurally related types of chemical messengers. Only cells that express the correct receptor can bind a particular messenger.
Not all cells express the same receptors, which leads to selective expression and specificity/ cell type/ tissue/ organ
Individual cells with the SAME receptor can also have a variety of responses based on,
Cell type
Intracellular signaling cascade coupling (ex. GLUT 1 GLUT 4)
Density of receptors
Structural integrity (defective or absent)
The more selective a receptor is
you are going to have a decreased amount of binding but a more specific response
What are examples of receptor ligand specificity?
AIS
Androgen Insensitivity Syndrome
What is AIS?
XY karyotype
Testosterone is secreted but defective or absent receptor, resulting in no masculinizing effects of testosterone
Default biological gender is female
What are receptor families?
There are many subtypes of a receptor “family”
Enables selectivity of drugs while decreasing unwanted side effects
Varied response due to receptor
Ex. ACh, NE, GLUT
What are examples of receptor families?
Acetylcholine, Norepinephrine, glucose transports
What is receptor - affinity?
The degree a receptor binds to a chemical messenger is determined by the affinity
Chemical structure
Electrical charge
At a higher affinity
bind at lower conc.
And may be effective at a lower therapeutic dose
At a lower affinity
Bind at higher conc
Greater therapeutic dose
What is receptor saturation?
The degree to which receptors are occupied by messengers. If all are occupied, the receptors are fully saturated; if half are occupied, the saturation is 50% and so on
In saturation, as ligand concentration increases
Increases binding of receptors
Increases saturation
The maximum response of a ligand is due to
number of receptors available and bound
At a given concentration (X) of saturation
high affinity receptors bind more messenger
going to plateau once they’ve all bound
At a given concentration (X) of competition
Descresing amount of receptors bound by endogenous ligand
Decreasing that response
Ligands can be
agonist or antagonist
What is receptor - competition?
Ability of an exogenous molecule to compete with the endogenous or native ligand for binding site
What is an agonist?
Ligand that mimics or increase the action of endogenous substance
What is an example of an agonist?
Nasal spray (phenylephrine)
Mimics E -> vasoconstriction and nasal hypo secretion
What is an antagonist?
Molecule binds receptor and inhibiting activation occuring
What is a beta-blocker?
Decreases heart rate, vasodilation causing decrease in blood pressure
What are antihistamines?
Inhibit histamine release by mast cells causing decrease in allergic response
What is the regulation of receptors via down regulation?
Decrease in overall number of cell receptors for a specific ligand
Usually due to chronic exposure to large amounts of ligand
Desensitization
DM II
What is the internalization of receptors via receptor-mediated endocytosis?
Prolonged exposure to agonists often results in endocytosis of receptors
How is DM II involved in regulation of receptors via down-regulation?
Glucose, cells get used to having it around so they down regulate glucose receptors. Person thinks they need more, eat more, more down regulation.
What is up regulation?
Cells increase numbers of receptors due to low amounts of ligand
Increases sensitivity
What is down regulation?
A decrease in the total number of target-cell receptors for a given messenger; may occur in response to chronic high extracellular concentration of the messenger
Decrease number of hormone receptors decreases sensitivity
What is the regulation of receptors via up regulation?
Cells increase number of receptors due to low amounts of ligand causing increase in sensitivity
What is regulation of receptors via down regulation?
Target cells lose receptors in response to the hormone
What does the sensitivity of target cells depend on?
Part on number of receptors
Factors that affect signal transcription or gene transcription
What are signal transduction pathways?
Specific sequences of events (steps) and chemical molecules involved in the pathway that respond to receptor activation
What are lipid soluble messengers?
Includes steroids, TH
Majority bind intracellularly on nuclear receptors
Slower but longer-lasting response
One receptor can impact multiple genes causing change in transcription activity
What are the components of signal transduction pathways?
Lipid-soluble messengers
Water-soluble messengers
What is receptor activation?
Plasma membrane receptors have a complex/ complicated system due to the multiple steps involved
What are the PM effects of receptor activation?
Permeability altered, transporter properties, and/or voltage shifts
What are the potential cellular responses of receptor activation?
Metabolism altered, secretory activation, rate of proliferation & differentiation, contractility, etc
What does an activated receptor do?
Increases or decreases gene activity
What are exceptions to lipid soluble messengers?
Binds plasma membrane, bind inactive cytosolic receptors
In lipid-soluble messengers, one receptor can impact multiple genes which
changes transcription activity
What is the speed and response of lipid-soluble messengers?
Slower but longer-lasting response
What is the first messenger?
Ligand in the extracellular fluid that binds to plasma membrane receptor
What is the second messenger?
Intracellular molecule generated in response to 1st messenger
Ex.) cAMP, Ca 2+, IP3, DAG, etc
What are protein kinases?
An enzyme that phosphorylates other proteins by transferring the high energy 3rd phosphate group from ATP
What are activated proteins?
Transporters, metabolic enzymes, contractile proteins
Cells respond to 1st messenger
Describe Water-soluble messengers
Water soluble ligands bind to extracellular receptors
Ex.) Polypeptide hormones, NTs, Paracrine, autocrine substances
Water-Soluble messengers have a broad range of receptors that include
Ion channels, GPCRs, Receptors with intrinsic kinase activity, etc
Receptors activate intracellular signaling cascades that affect cell function
These receptors can (+) activate downstream mediators , which affect DNA transcription, but also have many other effects in the cell
Faster, but shorter-lasting response
Describe the timing and response of water-soluble messengers
Faster but shorter-lasting response
What is the classification of receptors based on?
Their locations and signal transduction pathways they use
What are intracellular receptors function?
(Lipid soluble messengers)
Function in the nucleus as transcription factors or suppressors to alter the rate of transcription of particular genes
What are plasma membrane receptor types?
Ligand gated ion channels
Function as enzymes, receptor tyrosine kinases
Bound to and activate cytoplasmic janus kinases
G protein couple receptors activate G proteins
In signaling by receptors that are ligand-gated ion channels we find
Binding of ligand gated ion channels
Causes conformational change of receptor and opening or closing of channel through plasma membrane
Abundant in nervous and muscle tissues
Ions diffuse into/out of cell.
Ex. Na+, K+, Ca2+, Cl-
Often results in a change in the MP of a cell
Where is signaling by receptors that are ligand gated ion channels abundant?
Nervous and muscle tissue
In signaling by receptors that function as enzymes, some receptors have intrinsic enzyme activity such as?
Usually protein kinases that phosphorylate tyrosine residues
*receptor tyrosine kinases
Guanylyl cyclase which catalyzes cGMP is an exception
What is the sequence of events of intrinsic enzyme binding
1st messenger binds tyrosine kinase receptor -> conformational change -> activation of enzymatic cytoplasmic receptor -> autophosphorylation of receptor of tyrosine residues -> phosphotyrosines become docking sites for cytoplasmic proteins -> bind and activate other proteins
Signaling by receptors that function as enzymes causes what?
Cascade of events leading to activation of 1 or more signaling pathways & cytoplasmic proteins by phosphorylation
What are growth factors (Gfs)?
Cell proliferation/differentiation
Without Gfs neurons will NOT grow
Presence /absense of Gfs can decide if cells are viable or not
Signaling by receptors that interact with cytoplasmic janus kinases contain?
Several families of cytoplasmic protein kinases
-> non-receptor tyrosine kinases, SFKs (src), JAKs, etc
Ligand binds receptor that lacks intrinsic kinase activity
How does the ligand bind to a receptor that lacks intrinsic kinase activity?
1st messenger -> conformational change -> (+) JAK -> targets protein phosphorylation -> (+) transcription factors -> new protein synthesis
Cytokine signaling occurs via
receptors linked to JAKs
What is signaling by G-protein coupled receptors?
Superfamily (largest) of cell-surface receptors
Encoded by more than 1000 genes
Involved in virtually all physiological processes
What do GPCR signal transduction convert extracellular messages to?
Intracellular responses
What is the role of G-protein coupled receptors?
Play a major role in sensory stimuli & processing
Vision, olfactory, gustation, nociception, etc
AbNL GPCRs disorders include
Allergies, HTN, depression, obesity, CNS disorders
Over half of all medications are targeting GPCRs
Significant % of prescription medications directly or indirectly target GPCRs
What is the structure of GPCRs?
Intracellular, peripheral protein complex of 3 subunits -> alpha, beta, & gamma
What are the 3 subunits of GPCRs?
Alpha, beta, gamma
What do the beta and gamma subunits do?
Anchor complex to plasma membrane, anchor alpha unit (dissociates)
May activate (stimulatory) or inhibit (inhibitory) (kinase activity)
The alpha subunit of GPCRs can bind?
GDP and GTP
What happens when GPCR alpha subunit binds to GTP?
Dissociates and couples to effector protein (ion channel or enzyme)
Structure almost always influences function
In GPCRs the water soluble is binding, WHY?
Being transported through blood, which is 90% water. More efficient to have water soluble
Messengers that are hydrophilic are
Metabolically efficient
Messengers that are water fearing (lipid soluble) are
dependent on carrier protein
What happens when the ligand binds to the GPCR?
Changes the receptor’s shape
Then activates an associated G-protein
Then activates effector proteins
Ex. Enzyme functions or ion channels
-Effect can either be (+) or (-)
What is the G protein system function?
Serve as a switch (on or off) to couple a receptor to an ion channel or to an enzyme in the plasma membrane
What are 2nd messenger systems (subfamilies) for GPCRs?
Cyclic AMP, IP3/DAG, Ca 2+, Arachidonic acid and Eicosanoids
1 receptor may be associated with more than or equal to 1 G protein type
G proteins may couple to multiple plasma membrane effector proteins
What can GPCRs directly regulate?
Opening and closing of ion gated channels
What are the common mechanisms by which receptor activation influences ion channels?
The ion channel is part of the receptor
A G protein directly gates the ion channel
A G protein gates the ion channel indirectly via production of a second messenger such as cAMP
What is Adenylyl cyclase?
Changes cytosolic ATP to cyclic AMP in response to an extracellular signal (2nd messenger)
Effector protein of Gs (stimulatory)
What is Gs?
Stimulates adenylyl cyclase, which increases levels of cAMP in the cell
(+) its effector protein (adenylyl cyclase) a PM protein
What is cyclic AMP?
A second messenger derived from ATP and triggers specific cellular changes in metabolic regulation
What does the 1st messenger in adenylyl cyclase and cyclic AMP do?
Epinephrine binds and (+) GPCR - Gs (stimulatory)
What happens to cAMP action when broken down to AMP?
cAMP action halts
What does altering the rate of 2nd messenger-mediated synthesis do?
Changes concentration of 1st messenger
Receptor numbers, etc
Altering the rate of action of cAMP phosphodiesterase
Why are coffee & tea stimulants?
Caffeine and theophyllinee inhibit phosphodiesterase activity which prolongs cAMP activity
What is cAMP phosphodiesterase?
An enzyme that breaks down cAMP halting the action of cAMP
What is the intracellular action of cAMP?
cAMP binds and activates cAMP - PKAs (dependent protein kinase A)
What happens when cAMP binds and activates cAMP PKAs (dependent protein kinase A)?
Phosphorylates various downstream targets
What does epinephrine do within the intracellular action of cAMP?
Adipocytes to break down stored triglycerides which increases blood glucose
Liver for glycogenolysis & gluconeogenesis, anabolism
What is glycogenolysis?
Breaks down glycogen to use parts to make glucose
When does epinephrine increase?
When physically active or stressed
Describe how there is a variety of cellular responses induced by cAMP?
Same 1st and 2nd messengers can have differing cellular responses
In signal amplification, 1 molecule of 1st messenger can lead to as much as 1 M of final product. What are the advantages/disadvantages?
Advantage: Only a little produces a lot, sets off big cascade. Energy efficient.
Disadvantage: Huge intracellular response, innate dangers. Gets out of control.
But they’re the same.
This is how very low amounts of substances can have significant effects systemically
Explain the differing effects & “types” of G proteins, how cAMP-PKAs pathways are involved
cAMP-PKAs can enter nucleus to alter gene expression
highly variable
Explain the differing effects & “types” of G proteins
Do all GPCRs stimulate cAMP?
Not all GPCRs stimulate cAMP; some inhibit adenylyl cyclase
Explain the differing effects & “types” of G proteins, explain Gi protein activation
Gi (inhibitory) protein activation -> decreases cAMP levels
Decreases the rate of phosphorylation of cytoplasmic proteins
What is the control of ion channels by G proteins?
Ion channels themselves can be the “effector protein” for a G protein complex
With direct or indirect regulation
If you have Gs then you have
Gi
What is the direct regulation of ion channels of G protein
G protein channel interaction
No 2nd messenger involved
What is the indirect regulation of ion channels by G proteins
Ex. PKA phosphorylates a plasma membrane ion channel causing opening of channel
2nd messengers utilized
What does Gq protein activate?
Phospholipase C
What happens when Gq protein activates phospholipase C?
Increases IP3 and DAG (diacyl glycerol) synthesis
What do IP3 and DAG do?
For together to activate enzymes which increase intracellular calcium levels
2nd messengers
What is phospholipase C?
plasma membrane effector enzyme
phosphatidylinositol bisphosphate (PIP2) (PM phospholipid)
What is diacylglycerol (DAG)?
A second messenger produced by the cleavage of a certain kind of phospholipid in the plasma membrane
What is inositol triphosphate (IP3)?
A second messenger that functions as an intermediate between certain signaling molecules and a subsequent second messenger, Ca2+, by causing a rise in cytoplasmic Ca2+ concentration
PLC is what?
A plasma membrane effector enzyme
DAG and IP3 are what?
Both 2nd messengers
DAG -> protein kinase C
What does Gq (G protein) activate?
PLC
PLC is a PM effector enzyme
What does DAG activate?
Protein kinase C
What does cytosolic IP3 bind to?
Receptors located on endoplasmic reticulum
Within inositol triphosphate, what happens when cytosolic IP3 binds to receptors located on endoplasmic reticulum?
Ligand gated Ca2+ channels open when bound to IP3
which causes increase in cytosolic Ca2+ levels
Sequence of events is dependent on specific pathway
How does Ca2+ behave as a 2nd messenger?
Can be increased or decreased causing the cytosol to elicit a cellular response
Normally cytosolic Ca2+ levels are
Extremely low
Maintained via active transport pumps in plasma membrane and organelles
What does the large electrochemical gradient favor in regard to Ca2+ as a second messenger?
Diffusion of Ca2+ into the cytosol
A stimulus to the cell can alter
ICF Ca2+ levels
Directly opens channel to influx Ca2+ levels
Or indirectly allows release of Ca2+ to cytoplasm
Altering Ca2+ intracellular levels, explain how electrical stimuli can open plasma membrane Ca2+ channels
Open Ca regulated ion gates on organelles
Ca2+ induced - Ca2+ release
Fuels muscle contraction
What does Ca2+ have the ability to do?
Ca2+ has the ability to bind cytosolic proteins
Ca2+ has the ability to bind cytosolic proteins causing
conformational change causing activation of calcium/troponin for muscle contraction
The conformation change alters affinity
How is Calmodulin involved in altering Ca2+ intracellular levels?
Calmodulin binding is found in all cells
Involved in muscle contraction
(+) or (-) of calmodulin-dependent protein kinases leads via phosphorylation to either activate or inhibit cellular protein responses to 1st messenger
Explain Calcium as a second messenger, in which stimulation of a cell leads to an increase in cytosolic Ca 2+ concentration
1st. Receptor activation
Plasma membrane Ca2+ channels open in response to a first messenger; the receptor itself may contain the channel, or the receptor may activate a G protein that opens the channel via a second messenger
Then
Ca2+ is released from the endoplasmic reticulum; this is typically mediated by IP3
Then
Active Ca2+ transport out of the cell is inhibited by a second messenger
2. Opening of a voltage-gated Ca2+ channel
Explain calcium as a second messenger by which an increase in cytosolic Ca2+ concentration induces the cell’s responses
- Ca2+ binds to calmodulin. On binding Ca2+, the calmodulin changes shape and becomes activated, which allows it to activate or inhibit a large variety of enzymes and other proteins. many of these enzymes are protein kinases
- Ca2+ combines with Ca2+ binding proteins other than calmodulin, altering their functions
What is Arachidonic acid?
Polyunsaturated fatty acid of the plasma membrane phospholipids
Lipid component of plasma membrane
What are Eicosanoids?
Produced from Arachidonic acid in many cell types for many reasons
Liberate arachnidoic acids from plasma membrane
In arachidonic acid and eicosanoids what stimulus binds receptor?
Neurotransmitters, hormone, durg
-> PLA2 phospholipase activation
-> Arachidonic acid
Liberates arachidonic acid
What are the types of eicosanoids?
Cyclic endoperoxides
Pls (prostaglandins)
TXAs (thromboxanes)
LTs (leukotrienes)
What does PLA2 cleave?
arachidonic acid from the plasma membrane
What are the two metabolic pathways of PLA2?
Cyclooxygenase (COX) pathway
Lipoxygenase pathway
What are PGs (part of the COX pathway)?
Prostalgandins
PGA, PGE
Pain, fever, blood clotting, inflammation
What are TXAs (part of the COX pathway) ?
Hemostasis
Aspirin, NSAIDs block cox
Aspirin -> stroke, inhibits blood clotting, decrease risk of forming clots
What is cyclooxyrgenase (COX)?
Type of enzyme that helps encourage the production of prostaglandins (PGs)
What is the lipoxygenase pathway?
Pathway involved in converting AA into leukotrienes and lipoxins
LTs -> allergic response, inflammation
When steroids block PLA2 what happens?
Block all eicosanoid synthesis
decrease inflammation and allergic responses
Why are people advised to avoid taking aspirin or other NSAIDs prior to surgical procedure?
Going to really bleed
What do NSAIDs function as
analgesics
How NSAIDs work?
These agents decrease pain and inflammation by inhibiting action of cyclooxygenase
What do analgesics do?
Decrease perception of pain
What does anesthesia do?
Put someone in an unconscious state
What does an epidural do?
Inhibit ability to sense pain
What are amnesiacs?
Inhibiting ability to have short term recall of events
How are signal transduction pathways regulated via negative feedback HC?
Receptor activation must stop
Signal transduction pathways are often regulated how?
Via negative feedback HC
What happens when receptor activation stops in signal transduction pathways?
Causes decrease in 1st messenger amount binding to receptor
Leads to enzyme degradation, diffusion, uptake by neighboring cells
Causes decrease in cytosolic 2nd messenger levels
How do receptor structural changes occur in signal transduction pathways
Decreasing receptor affinity for 1st messenger
Phosphorylation halts further G protein binding
Internalization via receptor mediated endocytosis of receptor / 1st messenger complex
Why is receptor activation stopping and receptor structural changes important?
Critical to prevent overstimulation of a cell by a messenger and the detrimental effects that could occur as a result
Affinity to bind to a different protein occurs
Give an enzymatic breakdown example
Adenylyl cyclase -> change in cytosolic ATP to cAMP (2nd messenger)
