GPR81 is an orphan G-protein-coupled receptor that belongs to a family of hydroxy-carboxylic acid (HCA) receptors. Its endogenous ligand is L-lactate, a metabolite produced when glycolysis exceeds the capacity to oxidize pyruvate^1,2.

In addition to being a by-product of metabolism, lactate plays a role in insulin signaling, particularly in insulin mediated anti-lipolytic effects. Likewise, GPR81 is mostly expressed in adipose tissues and its activation results in inhibition of lipolysis and reduced hydrolysis of triglycerides to glycerol and fatty acids, suggesting that GPR81 may be an attractive drug discovery target for metabolic disorders⁴.

Beyond the control of adipocyte lipolysis, GPR81 is also involved in neuronal signaling, regulation of blood flow to the retina. The receptor is overexpressed in several cancer types where it appears to play a role in the adaptation to the ischemic tumor microenvironment⁵.

GPR81, like all other G protein coupled receptors, consists of seven transmembrane domains, in addition it possesses a highly conserved Cys-Glu-Ser-Phe motif in the second extracellular loop, essential for its function and six Cys residues at the extracellular domains that potentially form three disulfide bonds⁶.