GPR37 and GPR37L1 Are Receptors for the Neuroprotective and Glioprotective Factors Prosaptide and Prosaposin

Proc Natl Acad Sci U S A. 2013 Jun 4;110(23):9529-34. doi: 10.1073/pnas.1219004110. Epub 2013 May 20.

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.

Keywords: GPCR; MAPK; deorphanization; neurodegeneration; peptide.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Astrocytes / drug effects
  • Blotting, Western
  • COS Cells
  • Chlorocebus aethiops
  • Cyclic AMP / biosynthesis
  • Gene Knockdown Techniques
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Nerve Growth Factors / metabolism*
  • Nerve Growth Factors / pharmacology
  • Oxidative Stress / drug effects
  • Phosphorylation / drug effects
  • Polysorbates
  • RNA, Small Interfering / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Saposins / metabolism*
  • Saposins / pharmacology
  • Sulfur Radioisotopes / metabolism

Substances

  • GPR37 receptor, human
  • Nerve Growth Factors
  • PSAP protein, human
  • Polysorbates
  • RNA, Small Interfering
  • Receptors, G-Protein-Coupled
  • Saposins
  • Sulfur Radioisotopes
  • prosaptide
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Cyclic AMP