In GPCR signaling, what happens to the G protein after ligand binding?

• A. The beta-arrestin dimer inhibits the receptor.
• B. The G alpha subunit binds ATP and activates kinases.
• C. GDP is exchanged for GTP on the G alpha subunit.
• D. The G protein is released from the receptor and immediately deactivates.

Answer: (C)

When a ligand binds a GPCR, the receptor acts as a guanine nucleotide exchange factor for the G alpha subunit. In the inactive state, G alpha is bound to GDP and held with the beta-gamma dimer. The receptor promotes the release of GDP and the binding of GTP, switching G alpha to the active form. GTP-bound G alpha dissociates from the receptor (and from G beta-gamma) and goes on to regulate target proteins such as adenylyl cyclase or phospholipase C. The signal is turned off when GTP is hydrolyzed to GDP, returning G alpha to its inactive state so it reassociates with beta-gamma and the receptor. Beta-arrestin–mediated desensitization is a separate regulatory step that occurs later; G alpha does not require ATP to activate kinases, and deactivation is not immediate upon receptor binding.