G-Protein-Coupled Receptor Signaling

G-protein-coupled receptors are the largest family of cell-surface receptors, relaying signals through heterotrimeric G proteins to intracellular effectors.

Definition

G-protein-coupled receptor signaling is the process in which a ligand-activated seven-transmembrane receptor acts as a guanine-nucleotide exchange factor for a heterotrimeric G protein, whose subunits then regulate downstream effectors.

Scope

This topic covers the seven-transmembrane architecture of G-protein-coupled receptors, the activation cycle of heterotrimeric G proteins, the effectors they regulate such as adenylyl cyclase and phospholipase C, and how these pathways are amplified and terminated.

Core questions

• How does a G-protein-coupled receptor activate its G protein?
• What are the roles of the G protein alpha and beta-gamma subunits?
• Which effectors and second messengers do these pathways control?
• How is G-protein signaling switched off?

Key theories

G proteins as molecular switches

An activated receptor catalyzes exchange of GDP for GTP on the G protein alpha subunit, switching it on to regulate effectors until its intrinsic GTPase activity returns it to the off state.

Mechanisms

Ligand binding changes the conformation of a seven-transmembrane receptor so it promotes GDP-to-GTP exchange on the G protein alpha subunit, releasing it from the beta-gamma dimer. The activated subunits regulate effectors such as adenylyl cyclase, which makes cyclic AMP, or phospholipase C, which generates inositol trisphosphate and diacylglycerol. The signal is amplified through cascades and terminated when the alpha subunit hydrolyzes GTP and reassociates, aided by regulator proteins and receptor desensitization.

Clinical relevance

These receptors mediate responses to a vast range of signals and illustrate the switch-like logic of G proteins, making them a central model in cell signaling. The treatment here is descriptive and non-prescriptive.

History

Rodbell and Gilman established G proteins as the transducers linking receptors to effectors; Lefkowitz and Kobilka later defined receptor structure and the activated receptor–G protein complex, completing the molecular picture of this pathway.

Key figures

• Alfred Gilman
• Martin Rodbell
• Robert Lefkowitz
• Brian Kobilka

Seminal works

• gilman1987
• alberts2014

Frequently asked questions

What does a G protein do?

A G protein acts as a molecular switch that is turned on when it binds GTP and off when it hydrolyzes it to GDP, relaying the signal from the receptor to effector enzymes while it is active.

What second messengers do these receptors trigger?

Depending on the pathway, they commonly raise cyclic AMP through adenylyl cyclase or generate inositol trisphosphate and diacylglycerol through phospholipase C, which in turn releases calcium.