GPRC5B is a member of the large G-protein-coupled receptor (GPCR) superfamily of receptors that share a common structure of seven membrane-spanning domains, an extracellular N-terminal domain, an intracellular C-terminal domain, and many conserved residues^[1].

The ligand-binding domain of GPCRs is variable and the GPCRs have been divided into three classes based on the ligands that stimulate them, as well by key sequence motifs conserved within phylogenetically related subfamily members.

GPRC5B (also known as Retinoic Acid-Induced Gene 2 Protein (RAIG2)) is an orphan GPCR most closely related to the Class C GPCR family, based on homology. Class C GPCRs also includes the metabotropic glutamate, calcium-sensing receptor, GABA_B, and pheromone receptors.

Molecular biology approaches and knockout mouse studies reveal that GPRC5 family proteins have pivotal roles in cancer progression and control of metabolic homeostasis pathways^[2].

GPCR5B is known to be involved in the regulation of brain homeostasis, proteins related to adhesion or signaling, and remarkably, GPRC5B-mediated tyrosine-phosphorylation signaling cascades play a critical role in development of obesity and insulin resistance through dynamic sphingolipid metabolism^[3].

GPRC5B contains multiple phosphorylated residues in its carboxyl terminus. Phosphorylation of GPRC5b by the tyrosine kinase Fyn and the subsequent direct interaction with the Fyn Src homology 2 (SH2) domain were found to be critical for the initiation and progression of inflammatory signaling in adipose tissue^[4]. For example, a GPRC5B mutant lacking the direct binding site for Fyn failed to activate a positive feedback loop of nuclear factor κB-inhibitor of κB kinase ε signaling.