Cell Communication Flashcards
What is the intracellular response to extracellular signals?
Cell signaling
What is the conversion of information into a chemical change called?
Transduction
What four forms does information arrive in at cells?
Purely physical: (energy), light, sound, heat, pressure, and electricity
Chemical: neurotransmitters, hormones, eicosanoids, drugs, toxins
Cellular: gap junctions
Extracellular matrix molecules: collagen (think of platelet adhesion)
What are the 3 main methods of intracellular communication?
Endocrine
Paracrine
Autocrine
What are the strongest bonds to weakest? (Think chemistry)
Covalent > ionic > hydrogen > hydrophobic > van der Waals
What is it called when an enzyme associated with a signal receptor is activated and in turn, catalyzes the activation of many molecules of a second enzyme, each with activates a 3rd enzyme!?!
Amplification
What is it called when a transduction has a cell-specific receptor?
Specificity and sensitively
What is the ability of a signal-transfixing system to receive multiple signals and produce a unified response appropriate to the cell’s needs?
Integration
What two types of feedback are there?
Positive and negative
What is it when multiple components of signaling pathways are brought together on scaffold proteins to increase their local concentration and effects?
Compartmentalization
(I.e. ryanodine receptors)
What happens when a signal is present continuously?
Desensitization
What is the general flow through a G-protein-coupled receptor?
First Rabbit Eats the Sweetest Carrots
First messenger >
Receptor >
Effector >
Second messenger >
Cellular response
What are the 6 steps to the signaling pathway?
“Run To The Market Randy Travis!”
Recognition ~ of the signal by the receptor
Transduction ~ excellular message into an intracellular signal
Transmission ~ second messenger’s signal to the appropriate effector
Modulation ~ on/off switch
Response
Termination ~ usually accomplished by feedback control
What is it called when any chemical binds to a receptor?
Ligand (first messenger)
Causes a conformational change and initiates the signaling sequence
What is the final consequence of recognition and transduction?
Generation of a second messenger and/or the activation of a catalytic cascade
What two phases usually occur during transmission?
Amplification and integration
What are considered two methods of modulation?
Enzymatic phosphorylation or dephosphorylation reactions
How is feedback often accomplished?
Feedback control
This is the most common control system for maintaining homeostasis. If a factor is excessive or deficient, this feedback loop will produce a series of effects to reverse the change and return the value to its set point.
Negative feedback loop
In this control mechanism, a change in some factor will produce an enhanced or accelerated change in the same direction. Know as “vicious cycles”
Positive feedback loop
What are 3 examples of a positive feedback loop?
Childbirth
Blood coagulation
Opening of voltage-gated Na* channels to initiate and propagate
What is endocrine cell signaling?
A signaling molecule is secreted by a endocrine cell and transported through the circulation where it acts on a distant target cell
***hormones
What is paracrine cell signaling?
A chemical signal molecule is released by one cell and acts locally to regulate the behavior of a neighboring cell.
**neurotrasmitter cell signaling
What is autocrine cell signaling?
A cell responds to a signaling molecule that it also produced!
***NE stimulating alpha-2 receptor
What family of enzymes catalyzes the addition of a phosphate group to a molecule?
Kinases
What are examples of small hydrophilic chemical messengers?
Amino acids (GABA)
Biogenic amines (NE)
Choline Esters (Ach)
Iodothyronines (T4 & T3)
What are examples of lipophilic chemical (non polar) messengers?
Steroids
Eicosanoids
Miscellaneous
How many times does a G protein-coupled receptor span the plasma membrane?
7
About 1/2 to 2/3 of all drugs target what type of receptor?
G protein
How are G proteins turned on?
Ligand binds to the receptor-binding site
How are G-proteins turned off?
Intrinsic GTPase activity in the alpha subunit
What is the first messenger signal at the G protein-coupled receptor terminated by?
Diffusion of the ligand away from the receptor
Chemical modification of the receptor (typically phosphorylation) to desensitize the receptor
What does the Gs stand for?
G protein family
“S” is for stimulatory
*** alpha-a unit STIMULATES adenylyl cyclase
What does Gi stand for?
G protein family
“I” is for inhibitory! Alpha-i subunit inhibits adenylyl cyclase
What is Gq?
G protein family
“q” stimulate phospholipase (PLC)
Q = “Queer PLaCes”~ odd or different
What is the substrate of adenylyl cyclase? (Enzyme reaction)
ATP > cAMP
What is what is the substrate to Phospholipase C? Enzyme reaction..
PIP2 > IP3 + DAG
What is the substrate to phospholipase A2? Enzyme reaction?
Phospholipid > arachiodonic acid
What is arachidonic acid the precursor to?!
Prostaglandins
Thromboxanes
Leukotrienes
COX
Increased cAMP in cardiac myocytes does what?
Enhances contractility (beta 1 effects)
what does increased cAMP do in the smooth muscles of the airways and vessels?
Causes relaxation and dilation. (Beta 2 receptor effects)
Increased cAMP does what in platelets?
Reduces platelet aggregation.
What does increased cAMP do in the principal cells of the nephron?
Insertion of aquarium 2-water channels in the apical membrane
What are the two types of synapses in the human body?
Electrical and chemical
What type of responses do ionotropic receptors participate in?
Fast synaptic responses
What are examples of excitatory responses?
Na+ influx
Ca influx
Reduced K efflux
What are examples of inhibitory responses?
Increased K+ efflux
Cl- influx
Closure of Ca channels
What’s another name for transmembrane G protein-coupled receptors?
Metabotropic
What is the presynaptic terminal also called?
Axon terminal, synaptic bouton, and synaptic knob
Which protein in the docking complex of the presynaptic terminal senses calcium and leads to release of neurotransmitters?
Synaptotagmin
What is the primary neurotransmitter of peripheral efferent (motor) neural pathways?
Acetylcholine
At what sites is ACh the neurotransmitter?
NMJ
Autonomic ganglia
Terminal synapses of parasympathetic post ganglionic fibers
A few sympathetic post ganglionic fibers (sweat glands)
The non-neural cholinergic system
What is the synthesis of acetylcholine synthesis?
Glucose in nerve terminal > glycolysis converts glucose to pyruvate > pyruvate enters mitochondria > acetyl-CoA is created > acetyl-CoA is transported back into cytoplasm > choline is actively transported into presynaptic terminal > choline acetyltransferase catalyzes the formation of ACh from acetyl-CoA + choline
What is the rate limiting step to ACh synthesis?
Choline transport
What enzyme hydrolyzes ACh to acetate + choline?
Acetylcholinesterase
Where are NmAChRs found?
Skeletal muscle at the neuromuscular junction
**end plate depolarization and skeletal muscle contraction
Where are NnAChRs found?
Autonomic ganglia, chromaffin cells, and CNS
***Depolarization of post-synaptic post-ganglionic neuron
Secretion of catecholamines
Arousal, attention, and analgesia
What two agonist binding site must occur to elect a reaction in a nicotinic receptor?
Must bind with two alpha subunits
Where are M1 receptors found?
Autonomic ganglia (**excitatory response)
CNS (**arousal, attention, analgesia)
Where are M2 receptors found?
Heart: nodal tissue (slowed spontaneous depolarization ~ decreased chronotropy)
Heart: contractility: (decreased contractility ~ decreased dromotropy)
Where are M3 receptors found?
Smooth muscle (contraction)
GI (increased secretions)
Where are M4 receptors found?
CNS (**presynaptic auto-receptors > negative feedback to suppress ACh release)
**like alpha 2 receptors
Where are M5 located?
CNS (promotes dopamine release, dilation of cerebral arteries)
Which G receptor is associated with M1, M3, M5?
Gq ~ odd number for an odd/Queer receptor.
***Gq > PLC > IP3 > DAG > increase in Ca
What M receptors are associated with Gi?
M2 and M4
**Gi is inhibitory!! > inhibits AC > decrease in cAMP
What does the NMDA receptor have binding sites for?
Glutamate
Glycine
Magnesium
Ketamine
What is the primary excitatory neurotransmitter in the brain?
Glutamate
- motor neuron activation, pain pathway, hyperanalgesia pathway, memory formation, and cerebral neurotoxicity
What is the primary inhibitory neurotransmitter in the brain?
GABA
*play a role in arousal, attention, memory formation, anxiety, sleep, and muscle tone
What is the primary inhibitory neurotransmitter in the spinal cord?
Glycine
Renshaw cells > form inhibitory synapses on alpha motor nerves >self-limiting firing of alpha motor nerves
What two amino acids are interconvertible through the kreb’s cycle? The brain can easily convert one to the other!
GABA and Glutamate
What is glutamate synthesis?
Glutamine is transported out of a glial cell > transported into presynaptic terminal > in terminal, glutamine is converted to glutamate by glutaminase (on mitochondria membrane) > glutamate is transported and stored in vesicles
What is the rate limiting step in glutamate synthesis?
Glutaminase activity
What are the 3 types of ionotropic glutamate receptors?
N-methyl-D-asparate (NMDA)
a-amino-3-hydroxy-5-methyl-4-isoxazeole-propionic acid (AMPA)
Kainate receptors
What does full activation of a NMDA receptor requires what?
It’s A LOT!
Binding of TWO glutamates
Two glycine molecules
AND a depolarizing voltage change
“3 safety locks”
the phencyclide binding site in the NMDA receptor is a binding site for what meds?
PCP and ketamine
What is it called when you experience neuronal injury initiated by excessive glutamate receptor activity?
Excitotoxicity
What pathological disease processes is excitotoxicity (as in the NMDA) implicated in?
Huntington’s disease
Alzheimer’s disease
ALS
Stroke and trauma
Hyperanalgesia
Epilepsy
What is GABA synthesis?
Glutamine enters presynaptic terminal > in mitochondria, glutaminase converts glutamine to glutamate > back in cytoplasm, GABA is formed by decarboxylation of glutamate (this is by glutamic acid decarboxylase [GAD])
***GAD is NOT present in neurons that use glutamate as a neurotransmitter
What are GABAa receptors?
Ionotropic
* ligand gates Cl- channels.
> activated by the binding of two GABA molecules
***GABAa are the target of:
>benzos
> barbs
> prop
> etomidate
> volatile anesthetics
> majority of hypnotics!!!
What are GABAb receptors?
Metabotropic
> inhibitory still
What type of receptor is glycine only?
Ionotropic
**Co-activator of NMDA
What is a rare neurological disease that results from mutations in the glycine receptor?
Human startle disease
What two binding sites are located IN the NMDA RECEPTOR CHANNEL PORE?
Mg
ketamine/PCP
What are norepinephrine and epinephrine metabolized to?
Vanillylmandelic acid
What are the 5 biogenic amine neurotransmitters? **hint ~they have “ine” in them
> dopamine
norepinepherine
epinephrine
histamine
serotonin (5HT)
What are most biogenic amine neurotransmitter receptors?
Metabotropic
What is the exception to most amine neurotransmitters being Metabotropic receptors? What specific amine?
Serotonin ~ 5-HT3 receptor
What are all biogenic amine neurotransmitters synthesized from?
Amino acids
What are ALL catecholamines synthesized from?
Tyrosine
What is serotonin synthesized from?
Tryptophan
What is histamine synthesized from?
Histidine
What does hydroxylation do?
Add an OH group
What does decarboxylation do?
Removes a CO2 group
What is the order from Tyrosine to Epinephrine?
Tyrosine > L-Dopa > dopamine > norepinephrine > epi
Our friend Tyler (tyrosine) who loved hydroxycut (tyrosine hydroxylase) was such a Loser AND Dope (L-dopa). He got smart and started to remove Carbs (decarboxylase) from his diet but was still a dope (dopamine). Eventually he drank a some water, hydrated (dopamine hydroxylase) and became like N-E-other (norepinephrine) guy in school. Unfortunately he did some meth (n-methyltransferase) and became the EPI-tome of another high school dropout.
What is tyrosine hydroxylated to form?
L-DOPA
(Done by tyrosine hydroxylase)
***rate limiting step in catecholamine synthesis
What is L-Dopa decarboxylated by to form dopamine?
L-amino acid decarboxylase
What catalyzes dopamine to form norepinephrine?
Dopamine-B-hydroxylase
What catalyzes norepinephrine to epi?
N-methyltranferase
Where does the conversion of NE to E happen?
Cytoplasm
Where does the conversion from dopamine to NE happen?
Vesicle
Where does the conversion from tyrosine to L-Dopa happen
What two enzymes metabolize catecholamines?
Monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT)
What does MAO-A preferentially degrade?
Dopamine, epinephrine, and serotonin
What does MAO-B preferentially degrade?
Degrades dopamine more rapidly than serotonin and NE
What is the end-product to catecholamine metabolism?
Vanillymandelic acid
(To become this, NE and Epi must be processed by BOTH MAO and COMT ~ order of which doesn’t matter)
What is the most common screening test to establish the diagnosis of pheochromocytoma?
Catecholamine metabolites in the urine!
What is serotonin synthesis?
Tryptophan > (tryptophan hydroxlase) > 5-hydroxytryptophan > (L-amino acid decarboxylase) > serotonin
What are high levels of 5-HIAA consistent with?
Carcinoid tumors!
**5-HIAA is metabolic byproduct of serotonin.
Where is histamine synthesize in the periphery?
Mast cells and basophils
What is the most important mechanism by which catecholamines are removed from the synaptic cleft?
Reuptake
Where is the largest concentration of dopamergic neurons located?
Substantia nigra
*crucial for coordinating mov
* degeneration or dopaminergic neurons causes Parkinson’s
What are the 5 types of dopamine receptors?
D1, D2, D3, D4, D5
Which dopamine receptors activate PKA via adenylyl cyclase and cAMP?
D1 and D5!
Which dopamine receptors inhibit adenylyl cyclase and reduce PKA activity ~ this leading to decreased neuronal activity?
D2, D3, D4
What are the 3 main classes of adrenergic receptors?
Alpha 1:( a1A, a1B, a1D)
Alpha 2: (a2A, a2B, a2C)
Beta: (B1, B2, B3)
What does NE preferentially bind to?
a1, a2, and B1
what does Epi predominately stimulate at low concentrations?
Beta effects
What does Epi stimulate at higher concentrations?
Alpha 1 effects
What is the 5-HT3R?
An ionotropic serotonin receptor.
Nonselective cation channel ~ activation leads to rapid membrane depolarization
***this is where Zofran works as an ANTAGONIST
What are the two purine bases?
Adenine
Guanosine
What is a nucleotide?
Molecule composed of a 5 Carbon sugar (Pentose), a nitrogen base, and a least one phosphate group.
(ATP, ADP, AMP, GMP, GDP)
What are the main purinergic transmitters?
ATP, ADP, and adenosine
What is the mechanism of action of adenosine?
Protects tissues from damage. A strong increase in adenosine levels in the extracellular fluid is an emergency signal indicates an acute oxygenation deficiency (stoke, MI)
What does NO arise from?
Oxidation of guanidino group of L-arginine
What does generation of NO require?
NADPH ~ molecular oxygen
What are some traits about necrosis?
Processes: uncontrolled
Cell size: enlarged (swelling)
Nucleus: pyknosis > karyolysis
Plasma membrane: disrupted
Cellular contents: enzymatic digestion ~ may leak out of cell.
Adjacent inflammation: frequent
What are some traits about apoptosis?
Processes: genetically programmed
Cell size: reduced (shrinkage)
Nucleus: fragmentation
Plasma membrane: intact
Cellular contents: intact
Adjacent inflammation: no
What four ways does B1 stimulation support cardiac performance??
> Positive inotropy (contractility)
Positive lusitropy (“getting loose”! Relaxation)
positive chronotropy (heart rate)
positive dromotropy (conduction)
What does NO activate in smooth muscle?
Soluble guanylyl cyclase (sGC) ~ this catalyzes the conversion of GTP to cGMP
What is the synthesis of nitric oxide (NO)
Stress/ACh/serotonin/etc… stimulate cell and increase intracellular Ca > Ca combines with calmodulin and activates endothelial nitric oxide syntheses (eNOS) > eNOS produces NO from L-arginine > NO diffuses into smooth muscle cells and activates guanylyl cyclase
What is in the central nerve system?
Brain and spinal cord
What is in the peripheral nervous system?
All nerves and sensory structures outside of brain and spinal cord
How is the peripheral nervous system divided?
Somatic and autonomic
> Somatic: voluntary control of muscles
Autonomic: involuntary control of glands and smooth muscle
How is the autonomic system divided?
Sympathetic
Parasympathetic
And enteric
What is the SNS classically described as?
“Fight or flight”
What is the PNS system classically called?
“Feed and breed”
