G Protein-Coupled Receptor (GPCR)

These receptors thread the membrane seven times. Agonist binding rearranges the helical bundle, most visibly an outward swing of the sixth helix, opening a cavity on the inner face that a heterotrimeric G protein can enter. The receptor then acts as a nucleotide exchange factor, prompting the alpha subunit to swap GDP for GTP so that the alpha subunit and the beta-gamma pair separate and act on effectors. Which effector depends on the G protein family: Gs stimulates adenylyl cyclase and raises cyclic AMP, Gi lowers it, and Gq drives phospholipase C, inositol trisphosphate and calcium release.

The human genome encodes roughly 800 of them, and they are the target of something like a third of approved drugs. Peptide hormone receptors of interest here mostly fall into two families. The class B secretin-like receptors, including those for GLP-1, GIP, glucagon, GHRH and parathyroid hormone, carry a large extracellular domain that grips the C-terminal helix of the peptide while the peptide's N-terminus inserts into the transmembrane bundle to trigger activation. The ghrelin and melanocortin receptors belong to the larger class A family. Cryo-electron microscopy has resolved many of these receptor-G protein complexes since 2017.

That two-domain binding mode explains a persistent drug-design problem: the class B interface is large and mostly buried, so replacing a peptide agonist with a small molecule at these receptors has been far harder than at class A receptors with compact pockets. The same architecture explains desensitisation, since the phosphorylated tail is what arrestin reads.

A frequent overreach is describing a compound as acting through a named receptor when no receptor has been identified for it. BPC-157 is the clearest case: it is widely marketed with detailed signalling diagrams, yet no receptor has been established for it in humans or animals.