G-protein coupled receptor 3 is a protein that in humans is encoded by the GPR3 gene. The protein encoded by this gene is a member of the G protein-coupled receptor family of transmembrane receptors and is involved in signal transduction. GPR3 mRNA is broadly expressed in neurons in various brain regions, including the cortex, thalamus, hypothalamus, amygdala, hippocampus, pituitary, and cerebellum. GPR3 mRNA is also expressed in the eye, lung, kidney, liver, testes, and ovary, among other tissues. Individuals afflicted by Alzheimer's disease have in many cases, overexpression of the GPR3 protein in their neurons. Function GPR3 activates adenylate cyclase in the absence of ligand. GPR3 was first described as a constitutive activator of adenylate cyclase. This constitutive activity could be due to stimulation by a ubiquitous ligand that may be free, membrane-bound, or membrane-derived. Alternatively, they propose that this could also be due to basal Gs coupling. Various groups have since supported this initial finding of GPR3 constitutive activation and have proceeded to show similar Gs activity in GPR6 and GPR12. GPR3 is expressed in mammalian oocytes where it maintains meiotic arrest and is thought to be a communication link between oocytes and the surrounding somatic tissue. It has been proposed that sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC) are GPR3 ligands, however this result was not confirmed in a β-arrestin recruitment assay. Mice lacking GPR3 were found to develop late-onset obesity owing to decreased UCP-1 expression in brown adipose tissue and reduced thermogenic capacity. Brown adipose tissue Activation Brown adipose tissue (BAT), in contrast to bona fide white fat, can dissipate significant amounts of chemical energy through uncoupled respiration and heat production (thermogenesis). Metabolic substrates are consumed to fuel mitochondrial futile cycles and uncoupling protein 1 (UCP1)-dependent respiration to ultimately convert chemical energy to heat. Gs-signaling stimulates the recruitment of thermogenically competent beige adipocytes in the subcutaneous adipose depots. Exposure to environmental cold stimulates thermogenic catabolism of lipids and carbohydrates in brown adipose tissue (BAT). BAT activation is predominantly ascribed to the Gs-coupled family, which signals through increased cyclic AMP (cAMP). This class is exemplified by the β-adrenergic receptors (ADRB1, ADRB2, and ADRB3), which represent the canonical means of sympathetic, ligand-mediated thermogenic control. However, in the case of Gpr3, cold exposure increases the expression of this constitutively active receptor, which possesses innate signaling capacity and, thus, can modulate cAMP levels and thermogenic output without a ligand. Gpr3 expression must