GPR37 is processed in the N?terminal ectodomain by ADAM10 and furin

GPR37 is an orphan G protein-coupled receptor (GPCR) implicated in several neurological diseases and important physiological pathways the brain. We previously reported that its long N-terminal ectodomain undergoes constitutive metalloprotease-mediated cleavage shedding, which have been rarely described for class A GPCRs. Here, we demonstrate protease cleaves at Glu167?Gln168 a disintegrin metalloprotease 10 (ADAM10). This was achieved by employing selective inhibition, RNAi-mediated downregulation, genetic depletion of ADAM10 cultured cells as well vitro purified with recombinant ADAM10. In addition, restored knockout overexpression wild type but not inactive mutant Finally, postnatal conditional mouse neuronal found to reduce endogenous brain cortex hippocampus, confirming relevance sheddase. Additionally, discovered subject another step cells. Using site-directed mutagenesis, site (Arg54?Asp55) localized highly conserved region distal end contains recognition proprotein convertase furin. The furin confirmed using furin-deficient human colon carcinoma LoVo inhibitors. thus first multispanning membrane protein has validated substrate GPCR processed both unconventional processing may represent regulatory element GPR37.