Which combination of G-protein subunit(s) has highest affinity for adenylate cyclase (AC)?

Question

BlackTom AI · Accepted Answer

The active, Gα subunit carrying GTP (α·GTP) is the form that binds adenylate cyclase (AC) with highest affinity and modulates its activity.

Relevant knowledge points and concepts:
- Heterotrimeric G proteins consist of α, β, and γ subunits. In the resting state the α subunit is GDP-bound and associated with the βγ dimer (αGDP–βγ).
- Binding of an activated G-protein–coupled receptor (GPCR) promotes exchange of GDP for GTP on Gα, producing α·GTP.
- α·GTP undergoes a conformational change, dissociates from βγ, and directly interacts with downstream effectors. Gs α·GTP stimulates adenylate cyclase; Gi α·GTP inhibits adenylate cyclase.
- Gβγ can regulate other effectors (ion channels, some enzymes) but does not have high affinity for AC regulation in the canonical pathway.

Step-by-step reasoning:
1. Inactive state: Gα·GDP is bound to βγ (αGDP–βγ), forming the heterotrimer. This complex does not effectively bind or regulate AC.
2. Receptor activation: GPCR acts as a guanine nucleotide exchange factor (GEF) for Gα, causing GDP → GTP exchange.
3. Active state: Gα·GTP dissociates from βγ and exposes effector-interaction surfaces. This free α·GTP directly binds adenylate cyclase with high affinity and changes its catalytic activity (increase for Gs, decrease for Gi).
4. Termination: Intrinsic GTPase activity of Gα hydrolyzes GTP → GDP, returning Gα to the inactive α·GDP form that reassociates with βγ.

Why the correct answer is correct:
α·GTP is the active effector-binding state; adenylate cyclase is specifically regulated by the Gα·GTP forms (Gsα·GTP activates AC; Giα·GTP inhibits AC). Thus αGTP has the highest affinity for AC.

Why other options are incorrect:
- a (αGDP–βγ): this inactive heterotrimer does not bind/activate AC with high affinity.
- b (β–γ): βγ primarily modulates ion channels and some enzymes, not adenylate cyclase in the canonical AC regulation; affinity for AC is low/insignificant.
- d (αGDP): GDP-bound α is inactive and remains associated with βγ, so it does not effectively bind AC.

Conclusion: The highest affinity combination for adenylate cyclase is α·GTP, confirming answer c.

Which combination of G-protein subunit(s) has highest affinity for adenylate cyclase (AC)?单项选择题

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