GPR39 (G-protein coupled receptor 39) is member of the rhodopsin-like family of 7-transmembrane containing GPCRs and is closely related to the ghrelin/neurotensin receptor subfamily.

The human GPR39 gene encodes the full-length receptor (GPR39-1a). GPR39 is expressed in various tissues including adipose tissue, heart and thyroid but is most abundant in the pancreas, GI tract, liver and kidney. 

The GPR39 receptor is comprised of an extracellular N-terminus, seven membrane spanning loops, and an intracellular C-terminus. It also contains four cysteine residues in its extracellular domains. These have been shown to form two disulfide bridges which are conserved within all vertebrate GPR39 sequences with the exception that the first bridge is absent from the fish receptors.

Although GPR39 has a high degree of constitutive activity mediated through G_αq and G_α12/13 pathways, it has been discovered recently that Zn²⁺ serves as a ligand capable of activating the receptor. Following Zinc activation, both pathways are significantly enhanced and signaling occurs through the G_αs pathway as well.

GPR39 has been implicated in several pathologies: Disruption of the GPR39 gene is associated with impaired insulin secretion. GPR39 knockout mice exhibit decreased insulin levels and lower levels of insulin promoting factor-1 and HNF-1α in pancreatic islets. GPR39 knockout mice also exhibit lower levels of CREB and BDNF proteins that are important in neuronal plasticity and antidepressant response thus leading to depressive-like behaviors in animals.