GPCRs

G protein-coupled receptors (GPCRs) are the largest and diverse family of cell-surface receptors in humans. They detect a wide range of stimuli, including light, odors, hormones, and neurotransmitters, and transmit signals into the cell primarily through heterotrimeric G proteins.

Signaling in GPCRs begins when a ligand binds to the receptor, inducing a conformational change that promotes GDP-to-GTP exchange on the Gα subunit. This causes Gα-GTP to dissociate from the Gβγ dimer, and both components regulate downstream effectors such as adenylyl cyclase (altering cAMP levels), phospholipase Cβ (producing IP3 and DAG), and various ion channels. G proteins are classified into Gs, Gi/o, Gq/11, and G12/13 families, each linked to distinct signaling cascades. Arrestins can bind activated receptors, leading to desensitization and internalization, and can also initiate alternative signaling pathways independent of G proteins.

GPCRs share a characteristic structure of seven transmembrane helices, with extracellular regions for ligand binding and intracellular regions for G protein coupling. They comprise several major families, including rhodopsin-like (Class A), secretin-like (Class B), and glutamate-like (Class C), along with additional groups such as adhesion, frizzled, and taste receptors. Humans possess roughly 800 GPCR genes, many encoding receptors for endogenous ligands; a substantial subset remains orphans with unknown ligands or functions.

Pharmacologically, GPCRs regulate nearly all physiological systems and are the targets of a large proportion of approved drugs, spanning cardiovascular, nervous, metabolic, and immune processes. Ligands range from small molecules to peptides and antibodies. Drug discovery frequently leverages structural information and advances in receptor stabilization, with ongoing interest in biased signaling and receptor dimerization as therapeutic modulations.