G protein-coupled receptor 37-like 1 modulates astrocyte glutamate transporters and neuronal NMDA receptors and is neuroprotective in ischemia

Glia. 2018 Jan;66(1):47-61. doi: 10.1002/glia.23198. Epub 2017 Aug 10.


We show that the G protein-coupled receptor GPR37-like 1 (GPR37L1) is expressed in most astrocytes and some oligodendrocyte precursors in the mouse central nervous system. This contrasts with GPR37, which is mainly in mature oligodendrocytes. Comparison of wild type and Gpr37l1-/- mice showed that loss of GPR37L1 did not affect the input resistance or resting potential of astrocytes or neurons in the hippocampus. However, GPR37L1-mediated signalling inhibited astrocyte glutamate transporters and - surprisingly, given its lack of expression in neurons - reduced neuronal NMDA receptor (NMDAR) activity during prolonged activation of the receptors as occurs in ischemia. This effect on NMDAR signalling was not mediated by a change in the release of D-serine or TNF-α, two astrocyte-derived agents known to modulate NMDAR function. After middle cerebral artery occlusion, Gpr37l1 expression was increased around the lesion. Neuronal death was increased by ∼40% in Gpr37l1-/- brain compared to wild type in an in vitro model of ischemia. Thus, GPR37L1 protects neurons during ischemia, presumably by modulating extracellular glutamate concentration and NMDAR activation.

Keywords: Gpr37l1 knockout mice; Gpr37l1-GFP mice; MCAO; neuroprotection; prosaposin.

MeSH terms

  • Action Potentials / genetics
  • Amino Acid Transport System X-AG / metabolism*
  • Animals
  • Animals, Newborn
  • Aspartic Acid / pharmacology
  • Astrocytes / drug effects
  • Astrocytes / metabolism*
  • Brain / pathology
  • Disease Models, Animal
  • Exploratory Behavior / physiology
  • Gene Expression Regulation, Developmental / genetics
  • Hippocampus / cytology
  • Infarction, Middle Cerebral Artery / pathology
  • Infarction, Middle Cerebral Artery / physiopathology
  • Infarction, Middle Cerebral Artery / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • N-Methylaspartate / pharmacology
  • Neurons / metabolism*
  • Neurons / physiology
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Recognition, Psychology / physiology


  • Amino Acid Transport System X-AG
  • Gpr37l1protein, mouse
  • Receptors, G-Protein-Coupled
  • Receptors, N-Methyl-D-Aspartate
  • benzyloxyaspartate
  • Aspartic Acid
  • N-Methylaspartate