Signaling through G Protein Receptors Flashcards Preview

M2M Block Cards AJS > Signaling through G Protein Receptors > Flashcards

Flashcards in Signaling through G Protein Receptors Deck (33)

1. Draw the membrane topology a G protein-coupled receptor and identify the basic structural characteristics that mediate ligand binding and coupling to G proteins.
2. Explain how G protein-coupled receptors activate hetero-trimeric G proteins and diagram the GTP-hydrolysis cycle of G protein signaling.
3. Describe the function of second messengers in receptor signaling and give two examples for how they are generated by activated G proteins.
4. Explain how receptor activation leads to signal termination through receptor desensitization and coupling to additional pathways.
5. Give two examples of drugs that act through modulating different steps in a receptor-G protein-second messenger signaling cascade.



G protein coupled receptors have ____ transmembrane domains arranged into a barrel-like pore where the ligand binds. The amino terminus extends into the ___ while the carboxyl terminus extends into the ______. Loops that extended into the cytoplasm (_____) confer specificity for the G protein binding

7; ECF; cytoplasm; i-loops


Effector regulation is mediated by both free _____ and _____.

Alpha-GTP and Beta-Gamma subunits.


How are G proteins activated?

Binding of an agonist to the G protein coupled receptor (GPCR) triggers transfer of a GTP to the G-alpha subunit, replacing a GDP. The G-alpha is active when bound to GTP and can signal induce effector molecules.


How are G proteins deactivated?

The G-alpha subunit is a GTPase, which cleaves the GTP to GDP, inactivating the signaling pathway [Nucleotide Hydrolysis (GTPase)].


The CTX Cholera toxin affects CL- channels, which apparently are GPCR channels. How does this toxin work?

CTX: Cholera Toxin-ADP ribosylates G-alphas near the GTP binding site of the alpha subunit to inhibit GTPase activity thus converting the G protein to the active state even without receptor activation. [No deactivation]


How does the Bordella Pertussis (whooping cough) toxin work?

PTX: Pertussis Toxin-ADP ribosylates G-alpha i/o family near the C- terminus of alpha subunit to lock the G protein heterotrimer in the inactive state by preventing receptor coupling. [No activation]


What are the signaling molecules of the sympathetic nervous system? Differentiate between synaptic messenger and hormonal. What is the receptor?

1) norepinephrine (NE) released at synapses
2) epinephrine (adrenaline) released into blood by the adrenal glands

Adrenergic receptor


What is the signaling molecule of the parasympathetic branch? What is the receptor?

1) acetylcholine (Ach) released at synapses

2) muscarinic cholinergic receptor


The activation reaction (exchange of GTP for GDP) can also be catalyzed with the assistance of a ______.

Once the alpha unit is bound to GTP it ______ and both are available to act on effector proteins. The alpha unit has an intrinsic GTPase activity that eventually hydrolyzes the GTP to GDP (this can be assisted by ________). Once the alpha unit is again associated with GDP, it can be recycled back to the membrane and G protein coupled receptor.

guanine nucleotide exchange factor (GEF)

dissociates from the beta-gamma unit; GTPase activating proteins or GAPs


In the peripheral vasculature, Alpha1 adrenergic receptors bind _____ which causes the exchange of GDP for GTP on Gq alpha unit. Gq-GTP interacts with the ____ molecule which cleaves minor membrane lipid _____. This causes an increase in the second messengers ___ and ___ both which eventually stimulate ______ resulting in _____ of smooth muscles.

Norepinephrine; PLC (phospholipase C); PIP2; DAG and IP3; Ca channels; contraction

[peripheral vasoconstriction increases bp, shifts focus to heart, lungs. Flight/fight]


In the heart Beta adrenergic receptors bind ____ causing GDP/GTP exchange and the activation of the Gs alpha unit which binds to ______. This ___ it. AC creates ____, a second messenger, increasing levels in the cell, which in turn activate _____. _____ phosphorylates Ca channels, leading to influx of Ca. These steps lead to _____.

adenylyl cyclase (AC); activates;
protein kinase A (PKA);
contraction of cardiac muscle


Again in the heart, lets look at an m2 muscarinic cholinergic receptor. It receives parasympathetic input when acetylcholine binds the receptor, activating the ____ with GTP which binds AC and _____ leading to _____.

Gi protein; prevents an increase in cAMP; decreased heart rate


In a given target tissue, what two GCPR types would likely not be found together? Why?

Alpha 1 adrenergic and m3 muscarinic cholinergic receptors. Why? Both have Gq internal sequences and induce similar pathways. This would cause problems since parasympathetic and sympathetic innervation would cause the same result.


Gs =

Stimulatory G protein



Inhibitory G protein


Gq = ?

acts on PLPc (Phospholipase C)


What effect would metaprolol (B1 selective antagonist) have on heart rate?

decrease it [and subsequently blood pressure]


What effect would prazocin (Alpha 1 selective antagonist) have on bp?

decrease bp [block vasoconstriction response in periphery]


Phosphodiesterases degrade _____ into _____, which renders it unable to ______

cAMP; AMP; stimulate PKA

[cGMP-specific PDE inhibitors: Viagra (PDE5)]

[caffeine is a PDE inhibitor, which prevents downregulation of the pathway]


The Beta 1 Adrenergic receptor receives what neurotransmitter? Agonist binding does what?

Norepinephrine. Stimulates adenylyl cyclase(AC) cAMP production


The Alpha 1 Adrenergic receptor receives what neurotransmitter? Agonist binding does what?

Norepinephrine. Stimulates phospholipase C (PLC) Ca2+ and lipid signals.


The M2 muscarinic receptor receives what neurotransmitter? Agonist binding does what?

Acetylcholine. Inhibits adenylyl cyclase(AC) cAMP production.


The M3 muscarinic receptor receives what neurotransmitter? Agonist binding does what?

Acetylcholine. Stimulates phospholipase C (PLC) Ca2+ and lipid signals.


What two G proteins compete (symp/parasymp)? Describe the battle.

Binding of Ach to the M2 muscarinic receptor stimulates Gi-alpha which inactivates Adenylyl Cyclase. Binding of NE to the Beta1 adrenergic receptor releases Gs-alpha which stimulates AC. Whichever signal is stronger wins.

[Both of these G proteins (Gi and Gs) can be active at the same time! Both can bind AC, and whichever has the more dominant signallying “wins” and effects heart rate more.]


Talk about m2-muscarinic cholinergic receptor signaling by K+ channel activation in heart.

Finally we get to use the Gamma subunit. This binds GIRK, a G activated potassium channel. Binding by the gamma subunit opens the channel and potassium flows out, leading to membrane hyperpolarization and decreased excitability and a decrease in heart rate and contraction.


What is likely to happen through epinephrine binding of Beta-adrenergic receptors in the lung?

Smooth muscle relaxation leading to bronchodilation (and dilation of vasculature supplying blood to lungs,heart and muscle)

[epinephrine-->Gs-alpha-->AC--> increase cAMP--> increase PKA which inhibits smooth muscle contraction]


What is likely to happen through Ach binding of m3-muscarinic cholinergic receptors in the lung?


[Ach-->Gq alpha-->cascade--> Ca2+ release--> contraction]


Describe two ways the G signaling pathway can become desensitized.

1) GRK = kinase
GRK phosphorylates the cytoplasmic loops of the G protein coupled receptor--> inactivates it. These phosphorylated residues recruit a protein called beta arrestin. Binding of beta arrestin further prevents G proteins from associating with the receptor, preventing further signaling.

2) Beta arrestin also acts as an adaptor for endocytic machinery, which causes internalization of the entire receptor. Thus, the cell becomes less sensitive to ligand because of fewer receptors. These internalized receptors can then be degraded or re-sensitized and recycled.



is an antagonist of the beta adrenergic receptor which blocks the activation of the G protein with GTP. Thus, it prevents an increase in cAMP in response to Norepinephrine and lowers heart rate.



is an antagonist of the alpha1 adrenergic receptor which prevent Gq-GTP from interacting with PLC. This in turn prevents the creation of DAG and IP3 receptors.



is an acetylcholine antagonist that prevents activation of Gi protein with GTP and thus is an antagonist of parasympathetic signaling. This results in a shift of balance with the Gs protein, whereby Gs “wins” and cAMP levels increase, increasing muscle contraction of the heart.


PDE inhibitors – Caffeine, Theophyline, Milinirone, Rolipram, etc:

These target the phosphodiesterases (PDE) of the message pathway to activate signaling. PDEs degrade cAMP by cleaving it to AMP, which is not capable of activating PKA, and thus terminate signaling. Many of these PDEs are constitutively active. By inhibiting the terminator of the signal, PDE inhibitors are able to extend signaling.