GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin

Abstract

GPR37 (also known as Pael-R) and GPR37L1 are orphan G protein-coupled receptors that are almost exclusively expressed in the nervous system. We screened these receptors for potential activation by various orphan neuropeptides, and these screens yielded a single positive hit: prosaptide, which promoted the endocytosis of GPR37 and GPR37L1, bound to both receptors and activated signaling in a GPR37- and GPR37L1-dependent manner. Prosaptide stimulation of cells transfected with GPR37 or GPR37L1 induced the phosphorylation of ERK in a pertussis toxin-sensitive manner, stimulated 35 S-GTPγS binding, and promoted the inhibition of forskolin-stimulated cAMP production. Because prosaptide is the active fragment of the secreted neuroprotective and glioprotective factor prosaposin (also known as sulfated glycoprotein-1), we purified full-length prosaposin and found that it also stimulated GPR37 and GPR37L1 signaling. Moreover, both prosaptide and prosaposin were found to protect primary astrocytes against oxidative stress, with these protective effects being attenuated by siRNA-mediated knockdown of endogenous astrocytic GPR37 or GPR37L1. These data reveal that GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin.

Precocious cerebellum development and improved motor functions in mice lacking the astrocyte cilium-, patched 1-associated Gpr37l1 receptor

“…Conceivably, Gpr37l1 may be important in the activation of developing cerebellar glia, via still unknown ligands, whose production is temporally limited to the peri-and postnatal stages. Recently, the secreted neuro-and glioprotective glycoprotein prosaposin and derived peptides have been shown in vitro to activate the putative Gpr37l1 and Gpr37 receptors (22). Prosaposin and other secreted proteins are produced by Purkinje neurons of newborn mice, with very low expression in prenatal and adult stages (41)(42)(43)(44)(45).…”

“…G-protein-coupled receptors for the endothelin and bombesin peptides (17,20,21). Recently, the secreted neuro-and glioprotective glycoprotein prosaposin and derived peptides have been shown in vitro to interact with and activate both putative receptors (22).…”

The Parkinson's-disease-associated receptor GPR37 undergoes metalloproteinase-mediated N-terminal cleavage and ectodomain shedding

“…Based on these early findings, the research on GPR37 has mainly focused on strategies to improve its plasma membrane trafficking and to reduce the receptor-induced cell toxicity (Dunham et al, 2009;Gandía et al, 2013;Lundius et al, 2013;Dutta et al, 2014). Recently, GPR37, together with its closest homolog GPR37-like 1 (GPR37L1; Valdenaire et al, 1998), has been reported to act as a receptor for prosaposin and a prosaposin-derived peptide prosaptide (Meyer et al, 2013). These peptides, which possess neuroprotective and glioprotective effects (reviewed in Meyer et al, 2013), have been found to induce receptor internalization and to stimulate GPR37-mediated signalling in HEK293 cells and primary cortical astrocytes (Meyer et al, 2013).…”

G Protein-Coupled Receptors in Myelinating Glia

“…Moreover, Gpr37, like Gpr17, can couple to Gα i/o proteins [65], cAMP levels are accordingly elevated in Gpr37-/-brains and cultured oligodendrocytes, and pharmacological experiments implicate increased Epac/Raf/ERK signaling downstream of cAMP when Gpr37 function is lost [59]. Although prosaponin has been identified as a ligand for Gpr37 [65], this glycoprotein may not function in Gpr37-mediated oligodendrocyte development [64]. Thus, identification of binding partner(s) for Gpr37 in oligodendrocyte lineage cells is an important area of future research.…”

“…While Gpr17 and Gpr37 act at different stages, importantly, both GPCRs negatively regulate oligodendrocyte development: as in Gpr17 mutants, loss of Gpr37 leads to precocious oligodendrocyte differentiation [59]. Moreover, Gpr37, like Gpr17, can couple to Gα i/o proteins [65], cAMP levels are accordingly elevated in Gpr37-/-brains and cultured oligodendrocytes, and pharmacological experiments implicate increased Epac/Raf/ERK signaling downstream of cAMP when Gpr37 function is lost [59]. Although prosaponin has been identified as a ligand for Gpr37 [65], this glycoprotein may not function in Gpr37-mediated oligodendrocyte development [64].…”