G protein coupled receptors (GPCR or GPR) comprise a large superfamily of receptors characterized by a seven transmembrane domain structure and an ability to activate intracellular transducer G proteins. Over 800 GPCRs in five main families have been identified in eukaryotes on the basis of genomic sequence analysis^1,2. These receptors can be activated by hormones, neurotransmitters, odorants, light, or pheromones. Whereas the endogenous agonist is remains unclear or in dispute².

GPCRs mediated the signaling of extracellular stimuli to intracellular responses via activation of heterotrimeric G proteins and their subsequent interaction with effector proteins. GPCRs have been implicated in a number of physiological functions including development of anxiety, behavior, homeostasis, cognition, appetite, and drug addiction³.

The GPCR family contains a diverse group of cell-surface mediators of signal transduction, its size exceeding other cell-surface protein receptors including the tyrosine kinase receptors, guanylyl cyclase receptors and ligand-gated ion channels⁴.

GPR108 (LUSTR2), has a large extracellular domain of an amino-terminal hydrophobic signal peptide sequence, and a carboxy-terminal seven-transmembrane domain⁵. Previous studies showed that GPR108 is linked to nuclear factor κB (NF-κB) signaling⁶ and regulates and inflammatory immune response and cancer signaling⁷.

Recently, GPR108 has been identified as a highly conserved cellular entry factor for Adeno-associated virus (AAV), a widely used and clinically approved gene therapy vector⁸.