Glio- and neuro-protection by prosaposin is mediated by orphan G-protein coupled receptors GPR37L1 and GPR37

Glia. 2018 Nov;66(11):2414-2426. doi: 10.1002/glia.23480. Epub 2018 Sep 27.


Discovery of neuroprotective pathways is one of the major priorities for neuroscience. Astrocytes are natural neuroprotectors and it is likely that brain resilience can be enhanced by mobilizing their protective potential. Among G-protein coupled receptors expressed by astrocytes, two highly related receptors, GPR37L1 and GPR37, are of particular interest. Previous studies suggested that these receptors are activated by a peptide Saposin C and its neuroactive fragments (prosaptide TX14(A)), which were demonstrated to be neuroprotective in various animal models by several groups. However, pairing of Saposin C or prosaptides with GPR37L1/GPR37 has been challenged and presently GPR37L1/GPR37 have regained their orphan status. Here, we demonstrate that in their natural habitat, astrocytes, these receptors mediate a range of effects of TX14(A), including protection from oxidative stress. The Saposin C/GPR37L1/GPR37 pathway is also involved in the neuroprotective effect of astrocytes on neurons subjected to oxidative stress. The action of TX14(A) is at least partially mediated by Gi-proteins and the cAMP-PKA axis. On the other hand, when recombinant GPR37L1 or GPR37 are expressed in HEK293 cells, they are not functional and do not respond to TX14(A), which explains unsuccessful attempts to confirm the ligand-receptor pairing. Therefore, this study identifies GPR37L1/GPR37 as the receptors for TX14(A), and, by extension of Saposin C, and paves the way for the development of neuroprotective therapeutics acting via these receptors.

Keywords: GPR37; GPR37L1; PKA; Saposin C; astrocyte; astroprotection; cAMP; neuroprotection; orphan receptors; prosaptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Animals, Newborn
  • Astrocytes / drug effects*
  • Cell Movement / drug effects
  • Cells, Cultured
  • Cerebral Cortex / cytology
  • Colforsin / pharmacology
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / metabolism
  • Cyclic AMP / pharmacology
  • Embryo, Mammalian
  • HEK293 Cells
  • Humans
  • L-Lactate Dehydrogenase / metabolism
  • Nerve Growth Factors / pharmacology
  • Neurons / drug effects*
  • Neuroprotective Agents / chemistry
  • Neuroprotective Agents / pharmacology*
  • RNA Interference / physiology
  • Rats
  • Rats, Wistar
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Saposins / chemistry
  • Saposins / metabolism*
  • Water / pharmacology
  • Wounds and Injuries / drug therapy


  • Adjuvants, Immunologic
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Psap protein, rat
  • Receptors, G-Protein-Coupled
  • Saposins
  • prosaptide
  • Water
  • Colforsin
  • Cyclic AMP
  • L-Lactate Dehydrogenase