Which sequence correctly describes the steps of the G-protein regulatory cycle?

Which sequence correctly describes the steps of the G-protein regulatory cycle?

• A. drug binds to the receptor; conformational change/activation of the receptor occurs; the G-protein cycle is initiated with GTP replacing GDP on the alpha subunit; the alpha subunit dissociates from the beta-gamma subunit to activate the effector; GTP is hydrolyzed to GDP, returning the alpha subunit to its inactive state; the heterotrimer reassembles and recouples to the receptor
• B. drug binds to the receptor; GTP is replaced by GDP on the alpha subunit; the alpha subunit activates the receptor directly; the beta-gamma subunit remains bound; GDP is hydrolyzed; the complex detaches from receptor
• C. conformational change occurs after ligand binding, followed by receptor inactivation and immediate termination of signaling; no G-protein activation occurs
• D. the G-protein cycle begins with GTP binding to the receptor, leading to immediate effector activation without GDP exchange

Answer: (A)

Binding of a ligand to a GPCR triggers a conformational change that lets the receptor act as a guanine nucleotide exchange factor for the Gα subunit of the heterotrimeric G protein. This causes GDP to be released and replaced by GTP on Gα. With GTP bound, Gα dissociates from the Gβγ dimer, and both components go on to regulate their respective effectors to propagate the signal. The intrinsic GTPase activity of Gα then hydrolyzes GTP to GDP, returning Gα to its inactive GDP-bound state, which reassociates with Gβγ and the receptor to reset the cycle. The other options misstate this sequence in small but important ways: GDP is not replaced by GDP, and the alpha subunit does not activate the receptor directly; signaling begins with the receptor promoting GDP→GTP exchange on Gα. No G-protein activation would stop the cascade, and GTP binding does not occur on the receptor itself—GDP→GTP exchange happens on Gα before effector activation.

Binding of a ligand to a GPCR triggers a conformational change that lets the receptor act as a guanine nucleotide exchange factor for the Gα subunit of the heterotrimeric G protein. This causes GDP to be released and replaced by GTP on Gα. With GTP bound, Gα dissociates from the Gβγ dimer, and both components go on to regulate their respective effectors to propagate the signal. The intrinsic GTPase activity of Gα then hydrolyzes GTP to GDP, returning Gα to its inactive GDP-bound state, which reassociates with Gβγ and the receptor to reset the cycle.

The other options misstate this sequence in small but important ways: GDP is not replaced by GDP, and the alpha subunit does not activate the receptor directly; signaling begins with the receptor promoting GDP→GTP exchange on Gα. No G-protein activation would stop the cascade, and GTP binding does not occur on the receptor itself—GDP→GTP exchange happens on Gα before effector activation.