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

Abstract

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Proteolytic Cleavage of the Extracellular Domain Affects Signaling of Parathyroid Hormone 1 Receptor

“…Processing by MMPs and other metalloproteinases has been described previously for a limited number of other GPCRs, e.g. for β 1 -adrenergic receptor ( 33 ), endothelin B receptor ( 34 , 35 ), thyrotropin receptor ( 36 , 37 ), protease-activated receptor 1 (PAR-1) ( 38 , 39 ), GPR124 ( 40 ) and more recently for GPR37 ( 41 , 42 ). Apart from PAR-1 and the adhesion family receptor GPR124, where protease cleavage unmasks the endogenous ligand resulting in receptor activation, a functional consequence of protease cleavage has not been explicitly reported.…”

Proteolytic cleavage of the extracellular domain affects signaling of parathyroid hormone receptor 1

“…Processing by MMPs and other metalloproteinases has been described previously for a limited number of other GPCRs, i.e. for beta-adrenergic receptor 1 (32), endothelin B receptor (33,34), thyrotropin receptor (35,36), protease-activated receptor 1 (PAR-1) (37,38), GPR124 (39) and more recently for GPR37 (40,41). Apart from PAR-1 and the adhesion family receptor GPR124, where protease cleavage unmasks the endogenous ligand resulting in receptor activation, a functional consequence of protease cleavage has not been explicitly reported.…”

Emerging Roles for the Orphan GPCRs, GPR37 and GPR37 L1, in Stroke Pathophysiology

“…Both GPR37 and GPR37 L1 undergo constitutive a metalloproteinase cleavage of their N-terminus [ 38 , 46 , 47 ]. This phenomenon of ectodomain shedding has been extensively described for the following GPCRs: protease-activated receptors (PARs) [ 48 ] and adhesion receptors [ 49 ].…”

“…For GPR37, the signaling effects being mediated by the proteolytic processing of the receptors N-terminus were not assessed. It has, however, been established that its ectodomain cleavage is specifically modulated by the metalloproteinase’s ADAM10 and furin [ 47 ]. Interestingly, the proteolytically processed species of both GPR37 and GPR37L1 seem to dominate in vivo [ 38 , 47 ].…”

“…It has, however, been established that its ectodomain cleavage is specifically modulated by the metalloproteinase’s ADAM10 and furin [ 47 ]. Interestingly, the proteolytically processed species of both GPR37 and GPR37L1 seem to dominate in vivo [ 38 , 47 ]. This suggests that under physiological conditions, both receptors are being rapidly processed into their proteolytically cleaved counterparts.…”