What is the regulatory cycle of GPCRs?

• A. The receptor is internalized and degraded after ligand binding.
• B. The receptor hydrolyzes GTP spontaneously without activation.
• C. The receptor binds the ligand but does not activate G-proteins.
• D. The drug binds to the receptor; conformational change/activation of receptor; GTP replaces GDP on the alpha subunit; The alpha subunit disassociates from the beta-gamma subunits; beta-gamma subunits activated effector molecule; GDP replaces GTP on the alpha subunit and it recouples to the receptor and beta-gamma subunits.

Answer: (D)

The signaling cycle of GPCRs hinges on the receptor acting as a catalyst to activate a heterotrimeric G protein. When a ligand binds, the receptor changes shape and promotes the exchange of GDP for GTP on the G alpha subunit. This activation causes G alpha to dissociate from the beta-gamma dimer, and both parts go on to regulate downstream effectors. After the GTP is hydrolyzed back to GDP by the alpha subunit’s own GTPase activity, the alpha subunit rebinds GDP and reassociates with the beta-gamma subunits, returning the system to its resting state and ready for another round of signaling. Internalization or degradation of the receptor is a separate regulatory mechanism that modulates sensitivity over longer times, not the immediate signaling cycle. Likewise, G proteins do not spontaneously hydrolyze GTP to GDP in the absence of receptor-mediated activation; the receptor-catalyzed GDP-to-GTP exchange is essential for triggering the response.