Structure and function of serotonin GPCR heteromers

Abstract Serotonin (5-HT) receptors play a prominent role in the central nervous system, as they modulate various neuropsychological processes. 5-HT receptors and transmitters are key drug targets for many brain disorders, including schizophrenia, mood disorders, and migraines. All 5-HT receptors (except for 5-HT3) belong to family A of the G protein–coupled receptor (GPCR) superfamily. Here, we review current knowledge on the structural and functional characteristics of 5-HT homo- and heterodimers. GPCR dimerization is thought to involve interactions between extracellular domains via covalent bonding, between transmembrane domains, and/or between intracellular domains or C-terminal tails. Diverse experimental approaches suggest that 5-HT receptor heteromerization affects receptor trafficking, pharmacology, and function. Homodimerization occurs during protein synthesis in the endoplasmic reticulum or during protein maturation in the Golgi, ensuring proper protein folding. Heteromerization alters ligand binding and may affect the pharmacological profiles of ligands. Heteromer biased ligands selectively activate another signaling pathway than the one they would activate when binding the receptor monomer. In the D2R/5-HT2A heteromer, biased agonist action of the 5-HT2A agonists DOI and LSD leads to an active conformational state of 5-HT2A, which induces an allosteric D2R/5-HT2A interaction that augments D2R signaling. Functional cross talk between protomers of a heterodimer can lead to the modulation of both G protein–dependent and G protein–independent signaling pathways. In the 5-HT2A/mGluR2 complex, which is linked to schizophrenia, 5-HT2A agonists reduce the affinity of mGluR2 agonists, whereas mGluR2 activation increases the affinity of 5-HT2A agonists. While serotonin receptor heteromerization is well established, most studies have been performed in vitro. Further in vivo studies of these GPCR interactions are needed to fully assess their physiological roles and potentially lead to the development of new therapeutic agents.