Prosaposin receptor GPR37
Function
G-protein-coupled receptor that plays a role in several physiological pathways such as resolution of inflammatory pain and oligodendrocyte differentiation (By similarity). Acts as a receptor for several ligands including prosaposin, osteocalcin or neuroprotectin D1. Ligand binding induces endocytosis, followed by an ERK phosphorylation cascade (PubMed:11439185, PubMed:23690594). Acts as a receptor for osteocalcin (OCN) to regulate oligodendrocyte differentiation and central nervous system myelination. Mechanistically, plays a negative role in oligodendrocyte differentiation and myelination during development via activation of the ERK1/2 signaling pathway. Therefore, regulates the stability of myelin or resistance of myelin itself to demyelination. Upon activation by neuroprotectin D1 (NPD1), promotes the activation of phagocytosis in macrophages as well as the shift in cytokine release toward an anti-inflammatory profile, and thus helps to reverse inflammatory pain. In addition, the increased macrophage phagocytosis mediates protection against sepsis upon pathogen infection. Additionally, extracellular vesicles derived from efferocyte express prosaposin, which binds to macrophage GPR37 to increase expression of the efferocytosis receptor TIM4 via an ERK-AP1-dependent signaling axis, leading to increased macrophage efferocytosis efficiency and accelerated resolution of inflammation (By similarity). May also act as a maturation factor of LRP6, protecting LRP6 from the endoplasmic reticulum (ER)-associated protein degradation (ERAD) and thereby promoting the Wnt/beta-catenin signaling pathway (PubMed:28341812).
Post-translational modifications
The N-terminus is cleaved by ADAM10 metalloproteinase; mediating limited proteolysis leading to the release of receptor ectodomain by shedding (PubMed:26869225, PubMed:34042202). In addition, cleaved by FURIN between Arg-54 and Asp-55 (PubMed:34042202).
Ubiquitinated by PRKN in the presence of UBE2E1 and UBE2L3 in the endoplasmic reticulum. The unfolded form is specifically ubiquitinated by SYVN1, which promotes its proteasomal degradation and prevents neuronal cell death.
Sequence Similarities
Belongs to the G-protein coupled receptor 1 family.
Tissue Specificity
Expressed in brain and spinal cord, and at lower levels in testis, placenta and liver, but no detectable expression observed in any other tissue. When overexpressed in cells, tends to become insoluble and unfolded. Accumulation of the unfolded protein may lead to dopaminergic neuronal death in juvenile Parkinson disease (PDJ).
Cellular localization
- Cell projection
- Dendrite
- Synapse
- Cell membrane
- Multi-pass membrane protein
- Endoplasmic reticulum membrane
- Multi-pass membrane protein
Alternative names
Prosaposin receptor GPR37, Endothelin B receptor-like protein 1, G-protein coupled receptor 37, Parkin-associated endothelin receptor-like receptor, ETBR-LP-1, PAELR, GPR37