GM1 Is Cytoprotective in GPR37-Expressing Cells and Downregulates Signaling

Abstract

G-protein-coupled receptors (GPCRs) are commonly pharmacologically modulated due to their ability to translate extracellular events to intracellular changes. Previously, studies have mostly focused on protein–protein interactions, but the focus has now expanded also to protein–lipid connections. GM1, a brain-expressed ganglioside known for neuroprotective effects, and GPR37, an orphan GPCR often reported as a potential drug target for diseases in the central nervous system, have been shown to form a complex. In this study, we looked into the functional effects. Endogenous GM1 was downregulated when stably overexpressing GPR37 in N2a cells (N2aGPR37-eGFP). However, exogenous GM1 specifically rescued N2aGPR37-eGFP from toxicity induced by the neurotoxin MPP+. The treatment did not alter transcription levels of GPR37 or the enzyme responsible for GM1 production, both potential mechanisms for the effect. However, GM1 treatment inhibited cAMP-dependent signaling from GPR37, here reported as potentially consecutively active, possibly contributing to the protective effects. We propose an interplay between GPR37 and GM1 as one of the many cytoprotective effects reported for GM1.

Orphan G Protein-Coupled Receptor GPR37 as an Emerging Therapeutic Target

“…Lipid raft disturbance with methyl-β-cyclodextrin or cholesterol oxidase results in reduced GPR37­(tGFP) surface density and decreased cell viability in N2a cells . Furthermore, GPR37­(tGFP) was observed to form complexes with GM1 ganglioside when labeled with cholera toxin on the plasma membrane, which also suggested a protective mechanism of GPR37, GM1, and lipid rafts against toxic GPR37 aggregates observed in PD …”

“…66 Furthermore, GPR37-(tGFP) was observed to form complexes with GM1 ganglioside when labeled with cholera toxin on the plasma membrane, which also suggested a protective mechanism of GPR37, GM1, and lipid rafts against toxic GPR37 aggregates observed in PD. 140 In studies involving rats injected with kainic acid (KA), the expression of PSAP and GPR37 was found to alleviate the nerve damage caused by KA. 141 Moreover, in facial nerve transection, PSAP and GPR37 were shown to produce neurotrophic factors involved in neuronal repair in microglial and astrocytes.…”

Lipids in Neurodegenerative Diseases

“…Accordingly, Dei Cas et al [9] developed a very accurate and sensitive novel approach to measure LacCer synthase activity in vitro using deuterated glucosylceramide via liquid chromatography coupled with tandem mass spectrometry; this method has the advantage of avoiding the costs and discomforts of managing radiochemicals. On the other hand, one of the main gangliosides, GM1, which is particularly expressed in the central nervous system, was shown to interact and form a stable complex with GPR37 in the article by Hertz et al [10]. The authors showed the GPR37-dependent rescue effect of GM1 against MPP+, a common dopaminergic neurotoxin.…”