GPR156

GPR156 (G protein-coupled receptor 156), is a human gene which encodes a G protein-coupled receptor belonging to metabotropic glutamate receptor subfamily. By sequence homology, this gene was proposed as being a possible GABAB receptor subunit; however, when expressed in cells alone or with other GABAB subunits, no response to GABAB ligands could be detected. In vitro studies on GPR156 constitutive activity revealed a high level of basal activation and coupling with members of the Gi/Go heterotrimeric G protein family. In 2021, an article was reported that GPR156 modulates hair cell orientation in the cochlea. Also, it was proposed that GPR156 is related to congenital hearing loss. GPR156 in complex with any of the Gi/o heterotrimers regulates the hair cell orientation. In 2024, molecular structures of G-free and Go-bound GPR156 were characterized by using cryogenic electron microscopy.

== Structure == Among class C GPCR family members, GPR156 is unique because it lacks a large extracellular domain. Structural analyses revealed that the asymmetric binding of Go-protein to GPR156 triggers conformational change of its cytoplasmic face without altering dimer interface.  Although the inactive class C GPCRs undergo rearrangement of their dimeric interface, the agonist- and/or the positive allosteric modulator-bound class C GPCRs retain their dimeric interface upon G-protein binding. Thus, the G-free GPR156 is likely to represent an active state. Structural and functional analyses suggest that abundant endogenous phospholipids, receptor dimerization, and the G-protein binding-induced conformational change of the cytoplasmic face are the primary reasons for constitutive activation of GPR156. Phosphatidylglycerol further stimulates the activity of GPR156, which suggests the environmental changes of the phospholipid composition may regulate the GPR156 activity. thumb|G-bound GPR156 (PDB: 8IED) thumb|G-free GPR156 (PDB: 8IEI)