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

Abstract

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.

Protective effects of GPR37 via regulation of inflammation and multiple cell death pathways after ischemic stroke in mice

“…The high degree of homology between GPR37 and GPR37L1 suggests that they might share the same ligands, and moreover, KO of either receptor was found to result in increased seizure susceptibility, with genetic deletion of both receptors resulting in an even more dramatic increase in vulnerability to seizures (30). Given our findings that deletion of GPR37 increases damage induced by ischemia and the similar findings recently made for mice lacking GPR37L1 (29), it will be interesting in the future to explore whether loss of both these receptors together might result in even more profound susceptibility to ischemia-induced damage.…”

“…A recent paper (29) described a neuroprotective effect of the GPR37 relative GPR37L1, as evidenced by a regulatory role on astrocyte glutamate transporters, reduced NMDA receptor current, and increased neuronal death after ischemic stroke in GPR37L1 KO mice (29). These receptors share 42% identity and are both widely expressed in the brain (58,59).…”

“…Intriguingly, both prosaptide (23)(24)(25) and neuroprotectin D1 (26)(27)(28) have been reported to exert protective actions in rodent models of nerve injury or stroke. Moreover, a recent study reported that deletion of the GPCR GPR37-like 1 (GPR37L1), a relative of GPR37 that is expressed mainly in astrocytes, results in increased brain damage and cell death likely because of increased extracellular glutamate concentration and NMDA receptor activation (29). However, the various cellular and molecular roles that GPR37 may play following brain injury are unknown.…”

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

“…The sequence of TX14(A) is highly evolutionarily conserved (Supporting Information Figure S1). GPR37L1 is highly expressed by astrocytes, which also express low levels of GPR37 (Supporting Information Figures S2 and S3;Jolly et al, 2017;Marazziti et al, 2007;Smith, 2015;Zhang et al, 2014). GPR37L1 is highly expressed by astrocytes, which also express low levels of GPR37 (Supporting Information Figures S2 and S3;Jolly et al, 2017;Marazziti et al, 2007;Smith, 2015;Zhang et al, 2014).…”

“…A point mutation in GPR37L1 leads to a severe neurological phenotype which includes intractable epilepsy, lethal in some of the affected individuals (Giddens et al, 2017). Moreover, the deletion of GPR37L1 drastically increased the neuronal loss after an ischemic stroke (Jolly et al, 2017). Moreover, the deletion of GPR37L1 drastically increased the neuronal loss after an ischemic stroke (Jolly et al, 2017).…”