G-protein-coupled receptors (GPCRs), are the largest family of membrane proteins and mediate most of the physiological responses to hormones, neurotransmitters and environmental stimulants. At the most basic level, all GPCRs are characterized by the presence of seven membrane-spanning α-helical segments separated by alternating intracellular and extracellular loop regions¹. Orphan GPCRs is a group of GPCRs that their endogenous ligands remain unidentified and therefore their natural functions in doubt².

GPR12 is an orphan G protein-coupled receptor related phylogenetically, functionally, and pharmacologically with the cannabinoid system. It considered as a “constitutively active receptor” since it greatly stimulates adenylate cyclase in the absence of ligand-receptor interaction. GPR12 seems to couple Gαs as well as Gαi proteins since it stimulates baseline cAMP-dependent signaling by activating Gαs proteins, and also inhibits forskolin activated signaling through Gαi interaction³.

GPR12 expressed in the pituitary gland, in neurons in the frontal cortex, piriform cortex, thalamus, hypothalamus, hippocampus, amygdala, and olfactory bulb. It was found that GPR12 plays a significant role in energy balance. GPR12 knock out mice exhibit increase body weight and body fat mass.  In addition, overexpression of GPR12 leads to cancer cells migration and invasion via phosphorylation of Keratin 8⁴.

Furthermore, GPR12 has been identified as an inverse agonist of the phytocannabinoid cannabidiol (CBD)⁴.