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Link to original content: https://omim.org/entry/602583
Alternative titles; symbols
HGNC Approved Gene Symbol: GPR37
Cytogenetic location: 7q31.33 Genomic coordinates (GRCh38) : 7:124,743,885-124,765,792 (from NCBI)
G protein-coupled receptors (GPRs, or GPCRs) contain 7 hydrophobic transmembrane domains connected by hydrophilic intra- and extracellular loops. They transduce a variety of hormone, endogenous peptide, and neurotransmitter signals into intracellular effects via G proteins (see GPR1, 600239). To identify novel neuropeptide-specific receptor genes, Marazziti et al. (1997) sequenced random cDNAs derived from human frontal brain. One cDNA, named GPR37, encoded a predicted 613-amino acid protein with 7 hydrophobic domains and significant similarity to GPCRs. The authors isolated the genomic sequence of GPR37 and found that it is composed of 2 exons and spans approximately 25 kb. By Northern blot analysis, GPR37 is expressed in brain as a major 3.8-kb mRNA and a less abundant 8-kb mRNA; the 3.8-kb mRNA is also detected in liver and placenta.
By searching expressed sequence tags (ESTs) from a human hippocampus cDNA library for endothelin-B receptor (EDNRB; 131244) homologs, Zeng et al. (1997) cloned a GPR37 cDNA, which they called ET(B)R-LP for 'endothelin receptor type B-like protein'. The GPR37 protein is 27% identical to EDNRB. In situ hybridization and reverse transcriptase in situ gene amplification showed that GPR37 mRNA is particularly concentrated in Purkinje cells of the cerebellum and in neuronal cells of the hippocampus. Functional assays indicated that endothelin-1 (EDN1; 131240), endothelin-3 (EDN3; 131242), bombesin (see 137260), and neuropeptide Y (NPY; 162640) did not have an effect on mammalian cells expressing recombinant GPR37.
Marazziti et al. (1997) found that the sequence of a sequence tagged site (STS) previously mapped to 7q31 is contained within the GPR37 gene.
Imai et al. (2001) identified GPR37, which they called PAELR, as a protein that interacts with parkin (602544), the gene product responsible for autosomal recessive juvenile Parkinson disease (PDJ; 600116). When overexpressed in cells, PAELR tends to become unfolded, insoluble, and ubiquitinated in vivo. The insoluble PAELR leads to unfolded protein-induced cell death. Parkin specifically ubiquitinates PAELR in the presence of ubiquitin-conjugating enzymes resident in the endoplasmic reticulum and promotes the degradation of insoluble PAELR, resulting in suppression of the cell death induced by PAELR overexpression. Moreover, the authors showed that the insoluble form of PAELR accumulates in the brains of PDJ patients. They concluded that unfolded PAELR is a substrate of parkin and that the accumulation of PAELR may cause selective neuronal death in PDJ.
Unfolded PAELR is a substrate of the E3 ubiquitin ligase parkin. Accumulation of PAELR in the endoplasmic reticulum (ER) of dopaminergic neurons induces ER stress leading to neurodegeneration. Imai et al. (2002) showed that CHIP (607207), HSP70 (140550), parkin, and PAELR formed a complex in vitro and in vivo. The amount of CHIP in the complex increased during ER stress. CHIP promoted the dissociation of HSP70 from parkin and PAELR, thus facilitating parkin-mediated PAELR ubiquitination. Moreover, CHIP enhanced parkin-mediated in vitro ubiquitination of PAELR in the absence of HSP70. CHIP also enhanced the ability of parkin to inhibit cell death induced by PAELR. Imai et al. (2002) concluded that CHIP is therefore a mammalian E4-like molecule that positively regulates parkin E3 activity.
Prosaptides are synthetic peptides designed to functionally mimic the neuroprotective region of prosaposin (PSAP; 176801) (Meyer et al., 2014). By screening orphan neuropeptides for ligands that bound epitope-tagged GPR37 and GPR37L1 (617630), Meyer et al. (2013) identified prosaptide. Full-length prosaposin also bound both receptors, and both receptors were internalized following ligand binding. Both prosaposin and prosaptide induced Erk (see 601795) phosphorylation and protected primary mouse cortical astrocytes against oxidative stress. Knockdown of Gpr37 or Gpr37l1 via short interfering RNA attenuated the protective effect.
Imai, Y., Soda, M., Hatakeyama, S., Akagi, T., Hashikawa, T., Nakayama, K., Takahashi, R. CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity. Molec. Cell 10: 55-67, 2002. [PubMed: 12150907] [Full Text: https://doi.org/10.1016/s1097-2765(02)00583-x]
Imai, Y., Soda, M., Inoue, H., Hattori, N., Mizuno, Y., Takahashi, R. An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell 105: 891-902, 2001. [PubMed: 11439185] [Full Text: https://doi.org/10.1016/s0092-8674(01)00407-x]
Marazziti, D., Golini, E., Gallo, A., Lombardi, M. S., Matteoni, R., Tocchini-Valentini, G. P. Cloning of GPR37, a gene located on chromosome 7 encoding a putative G-protein-coupled peptide receptor, from a human frontal brain EST library. Genomics 45: 68-77, 1997. [PubMed: 9339362] [Full Text: https://doi.org/10.1006/geno.1997.4900]
Meyer, R. C., Giddens, M. M., Coleman, B. M., Hall, R. A. The protective role of prosaposin and its receptors in the nervous system. Brain Res. 1585: 1-12, 2014. [PubMed: 25130661] [Full Text: https://doi.org/10.1016/j.brainres.2014.08.022]
Meyer, R. C., Giddens, M. M., Schaefer, S. A., Hall, R. A. GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin. Proc. Nat. Acad. Sci. 110: 9529-9534, 2013. [PubMed: 23690594] [Full Text: https://doi.org/10.1073/pnas.1219004110]
Zeng, Z., Su, K., Kyaw, H., Li, Y. A novel endothelin receptor type-B-like gene enriched in the brain. Biochem. Biophys. Res. Commun. 233: 559-567, 1997. [PubMed: 9144577] [Full Text: https://doi.org/10.1006/bbrc.1997.6408]