Which of the following statements about G protein-coupled receptors (GPCRs) is correct?

The alpha subunit of G proteins determines whether they are stimulatory or inhibitory.

G proteins bind hormones directly before transmitting signals to receptors.

G proteins are active when bound to GDP and inactive when bound to GTP.

G proteins require the beta and gamma subunits to remain bound to the alpha subunit to transmit signals.

Which of the following statements about G protein-coupled receptors (GPCRs) is true?

G proteins can act as either inhibitory or excitatory based on the type of alpha subunit.

The three subunits alpha, beta, and gamma must remain together as a complex for G protein to function.

G proteins bind directly to hormones to become activated.

In the resting state, G proteins are bound to GTP.

All are true regarding G protein Except?

Active conformation has all three subunits

Alpha subunit has GTPase activity

G-Protein Coupled Receptors for UPSC-CMS: High-Yield Biochemistry Lessons

GPCR Basics - Receptor Superstars

Largest family of integral membrane proteins; crucial drug targets.
Structure: Single polypeptide chain spanning the membrane 7 times (7TM or serpentine receptors).
- Extracellular N-terminus: Often involved in ligand binding.
- Intracellular C-terminus: Interacts with G-proteins.
- Loops: 3 extracellular (EL1-3) & 3 intracellular (IL1-3) loops. IL3 is key for G-protein coupling.
Ligands: Diverse; e.g., biogenic amines, peptides, lipids, photons, odorants.
Function: Transduce extracellular signals into intracellular responses, regulating numerous cellular processes.

⭐ GPCRs constitute the largest family of cell surface receptors, targeted by nearly 30-40% of all modern drugs.

Activation Cycle - The Switch On

Initial State: G-protein (αβγ complex) inactive; Gα subunit bound to GDP.
Ligand Binding: Agonist binds to GPCR, causing its conformational change and activation.
GEF Activity: Activated GPCR serves as a Guanine nucleotide Exchange Factor (GEF) for the Gα subunit.
Nucleotide Exchange: Gα releases its bound GDP and binds a molecule of GTP (cytosolic GTP concentration is higher than GDP).
Subunit Dissociation: Binding of GTP induces a conformational change in Gα, causing its dissociation from the Gβγ dimer and the GPCR.
Effector Modulation: Both the activated Gα-GTP and the free Gβγ dimer can then interact with and modulate specific effector proteins (e.g., adenylyl cyclase, phospholipase C), initiating downstream intracellular signaling pathways.

GPCR G-protein activation cycle

⭐ The intrinsic GTPase activity of the Gα subunit, which hydrolyzes GTP to GDP, is crucial for self-limitation of the signal and termination of G-protein signaling (returning Gα to its inactive state).

G-Protein Families & Pathways - Signal Cascaders

G-proteins, heterotrimeric ($G\alpha, G\beta, G\gamma$) signal transducers, link GPCR activation to intracellular effectors. The $G\alpha$ subunit defines the family and pathway.

Family	$G\alpha$ Subunit	Primary Effector(s)	Second Messenger(s)	Key Downstream Effects / Examples
Gs	$G\alpha_s$	↑ Adenylyl Cyclase (AC)	↑ cAMP	PKA activation → metabolic enzymes, ion channels, gene expression
Gi/o	$G\alpha_i, G\alpha_o$	↓ AC; K+ channels (Gβγ)	↓ cAMP; ↑ K+ efflux	PKA inhibition; membrane hyperpolarization (e.g., M2 receptors)
Gq/11	$G\alpha_q, G\alpha_{11}$	↑ Phospholipase C-β (PLCβ)	$IP_3$, DAG, ↑ intracellular $Ca^{2+}$	PKC activation; $Ca^{2+}$-calmodulin dependent kinases; smooth muscle contraction
G12/13	$G\alpha_{12}, G\alpha_{13}$	RhoGEFs (e.g., LARG, p115)	Rho GTPase activation	Cytoskeleton organization (via ROCK), cell migration, proliferation

⭐ Cholera toxin constitutively activates Gs by ADP-ribosylation (↑cAMP), while Pertussis toxin inactivates Gi by ADP-ribosylation (blocks inhibition of adenylyl cyclase, or other Gi effects).

Regulation & Clinical Hits - Fine-Tuning & Fixes

Desensitization: Rapid ↓ response to agonist.
- Phosphorylation: By G-protein Receptor Kinases (GRKs) (agonist-occupied) or PKA/PKC.
- β-Arrestin binding: Promotes internalization & uncoupling from G-protein.
Internalization/Sequestration: Receptor endocytosis into vesicles.
Downregulation: ↓ Total receptor number with prolonged agonist exposure.
Resensitization: Dephosphorylation & receptor return to membrane.

⭐ Chronic agonist exposure leads to receptor desensitization, often mediated by G-protein Receptor Kinases (GRKs) and subsequent β-arrestin binding, leading to receptor internalization.

Clinical Hits:
- Cholera toxin: Constitutively activates Gαs → persistent ↑cAMP.
- Pertussis toxin: Inhibits Gαi → prevents Gαi signaling → ↑cAMP.
- Common drug targets: β-blockers, antihistamines, opioids, antipsychotics.

High‑Yield Points - ⚡ Biggest Takeaways

GPCRs: Seven transmembrane α-helices; couple to heterotrimeric G-proteins (α, β, γ).

Activation: Ligand binding causes Gα to exchange GDP for GTP, then dissociate.

Gs stimulates adenylyl cyclase (↑cAMP); Gi inhibits adenylyl cyclase (↓cAMP).

Gq activates phospholipase C, yielding IP3 and DAG, increasing intracellular Ca2+.

Termination: Gα's intrinsic GTPase activity; receptor desensitization (e.g., arrestin).

Key Toxins: Cholera toxin ADP-ribosylates Gs (constitutively active); Pertussis toxin ADP-ribosylates Gi (inactive).

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