Signalling by G protein-coupled receptors

Best to use on flashcard mode with answer with terms.

What are the 2 major classes of allosteric receptors?

Receptor tyrosine kinases

G protein coupled receptors

How do active GPCRs catalyse activation of G proteins?

Induce them to release the bound GDP and replace with GTP

How do GPCRs reduce activation energy for G protein activation?

Make it easier for GDP to escape from an inactive G protein.

What are the recurrent themes in signalling pathways (4 options)?

1. Extracellular surface of receptor is specific to the extracellular signal

2. Each class transmits information through the plasma membrane to activate intracellular enzyme activity

3. Each class of receptor recruits downstream intracellular proteins that are shared with other receptors (does not require its own cohort)

4. Receptors amplify signalling cascades.

What are the 2 important consequences of the dissociation of the trimeric G protein after GTP is bound to the alpha-subunit?

1. G protein dissociates from the G protein coupled receptor, freeing the receptor to activate another G protein (essential for amplification)

2. Alpha-GTP and beta-gamma subunits can now regulate their effectors.

What is the effect of acetylcholine release from the parasympathetic nervous system?

G protein coupled receptors are stimulated in the heart

Provokes coordinated response

slows heart rate and decreases force of contraction

What are the two major classes of allosteric receptors?

Receptor tyrosine kinases (RTKs) and G-protein–coupled receptors (GPCRs).

What is the common role of all allosteric membrane receptors?

To transmit conformational changes across the plasma membrane.

What serves as the “antennae” of the cell?

Membrane-spanning receptor proteins that recognise extracellular stimuli.

Who discovered cAMP as a second messenger?

Earl Sutherland.

Who discovered G proteins?

Marty Rodbell.

What major question led to the discovery of G proteins?

How glucagon stimulates cAMP formation without entering cells.

What happens when an extracellular signal binds to a GPCR?

A conformational change occurs that activates an intracellular G protein.

What do activated GPCRs catalyse?

Exchange of GDP for GTP on G proteins.

What are the four major Gα families?

Gαs, Gαi, Gαq, and Gα12/13.

What nucleotide is bound to inactive Gα?

GDP.

What is the rate-limiting step in G-protein activation?

Dissociation of GDP from Gα.

How do GPCRs activate G proteins?

They open the deep GDP-binding pocket, allowing GDP to leave and GTP to bind.

What causes the G protein to dissociate into subunits?

Binding of GTP to Gα.

What terminates G-protein signalling?

Intrinsic GTPase activity of Gα (hydrolysis of GTP → GDP).

What proteins accelerate GTP hydrolysis on Gα?

RGS (Regulators of G-protein Signalling) proteins.

Why does GPCR signalling amplify signals?

One GPCR can activate many G proteins during its activated lifetime.

What is the functional consequence of Gα–GTP separating from Gβγ?

Both can independently regulate downstream effectors.

Which GPCR transmembrane helices form the cytosolic cleft for G-protein binding?

TMDs 3, 5, 6, and 7.

Which Gα regions bind the γ-phosphate of GTP?

Switch I and Switch II regions.

What structural effect does γ-phosphate binding have on Gα?

Pulls switch regions inward, activating Gα and disrupting βγ binding.

What does cholera toxin do to Gαs?

Blocks GTPase activity → persistent activation → excessive cAMP.

What does pertussis toxin do to Gαi?

Prevents receptor–G-protein coupling, inhibiting activation of Gαi.

How does acetylcholine slow heart rate?

Activates Gi → βγ opens K⁺ channels and inhibits Ca²⁺ channels → hyperpolarisation.

What is the universal structural motif of GPCRs?

Seven transmembrane domains (7TM), extracellular N-terminus, cytosolic C-terminus.

Why were GPCR structures historically difficult to solve?

They are flexible membrane proteins that undergo conformational changes.

What signalling features are shared by RTKs and GPCRs?

Specific extracellular recognition, allosteric transmission, downstream enzyme activation, recruitment of shared proteins, and amplification cascades.