GPR37

Target id: 103

Nomenclature: GPR37

Family: Class A Orphans

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

This receptor has a proposed ligand; see the Latest Pairings page for more information.

Gene and Protein Information
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 613 7q31 GPR37 G protein-coupled receptor 37 19
Mouse 7 600 6 A3.1 Gpr37 G protein-coupled receptor 37 8
Rat 7 603 4q22 Gpr37 G protein-coupled receptor 37
Previous and Unofficial Names
EDNRBL
EDNRLB
PAELR
hET(B)R-LP
G-protein coupled receptor CNS1
parkin-associated endothelin B-like receptor
Endothelin B receptor-like protein 1
Database Links
Specialist databases
GPCRDB gpr37_human (Hs), gpr37_mouse (Mm), gpr37_rat (Rn)
Other databases
Ensembl Gene
Entrez Gene
GeneCards
GenitoUrinary Development Molecular Anatomy Project
HomoloGene
InterPro
KEGG Gene
NeXtProt
OMIM
PharmGKB Gene
PhosphoSitePlus
Protein Ontology (PRO)
RefSeq Nucleotide
RefSeq Protein
TreeFam
UniProtKB
Wikipedia
Natural/Endogenous Ligands
prosaposin
Comments: Proposed ligand, single publication

Download all structure-activity data for this target as a CSV file

Agonists
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Affinity Units Reference
neuropeptide head activator Hs Agonist 8.0 – 8.5 pEC50 15
pEC50 8.0 – 8.5 (EC50 1.1x10-8 – 3.3x10-9 M) [15]
prosaptide {Sp: Human} Hs Agonist 8.1 pEC50 12
pEC50 8.1 (EC50 7x10-9 M) [12]
Agonist Comments
Although it was reported that mammalian tissues contain a peptide of identical amino acid sequence to Hydra head activator [1] and that head activator is an agonist of GPR37 [15], there is currently no evidence for the presence of a gene encoding this peptide in any sequenced genome. However, the C-terminal sequences of head activator and prosaptide are similar, which may explain the activity of head activator on GPR37
Primary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family Adenylate cyclase inhibition
Comments:  Pertussis toxin pre-treatment completely inhibited the ability of prosaptide to stimulate ERK phosphorylation in GPR37-transfected cells [12]. It has been reported that neuropeptide head activator signal transduction through GPR37 required Ca2+ influx through a channel of the transient receptor potential (TRP) family and activation of the Ca2+-dependent calmodulin kinase and phosphoinositide 3-kinase [15].
References:  15
Tissue Distribution
Brain (corpus callosum, substantia nigra, caudate nucleus, amygdala, hippocampus, hypothalamus, thalamus and subthalamus nucleus), liver, placenta, pancreas and kidney. Not detectable in lung, heart or skeletal muscle.
Species:  Human
Technique:  Northern blot
References:  19
Neuronal cells of the cerebellum, especially in Purkinje cells of the cerebellum, and neuronal cells of the hippocampus, including pyramidal cells of Ammon's horn and granule cells of the dentate gyrus.
Species:  Human
Technique:  In situ hybridisation
References:  19
Brain (corpus callosum, medulla, putamen, caudate nucleus and cerebellum). Not detected in kidney, skeletal muscle, heart, lung or pancreas.
Species:  Human
Technique:  Northern blot
References:  9
Muscle-myenteric nerve layer of gastrointestinal tract.
Species:  Mouse
Technique:  RT-PCR
References:  4
Striatal presynaptic membrane.
Species:  Mouse
Technique:  Western blot
References:  11
Brain and testis. Not detected in liver, heart, spleen, lung, skeletal muscle or kidney.
Species:  Mouse
Technique:  Northern blot
References:  8
Tissue Distribution Comments
The mRNA level of GPR37 in rat striatum decreased within 2 hours after methamphetamine treatment [14]. The expression of GPR37 in MN9D cell line was upregulated after 0.5 hour of exposure to the neurotoxin 1-methyl-4-phenylpyridinium (MPP+ and remained upregulated up to 48 hours [18].
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
GPR37 association with cell survival.
Species:  Mouse
Tissue:  Primary cortical astrocytes.
Response measured:  Protection from H2O2-induced death, ERK phosphorylation.
References:  12
Ligand/receptor interaction.
Species:  Human
Tissue:  HEK-293T cells cotransfected with GPR37 and syntenin-1.
Response measured:  Internalisation of epitope-tagged receptor, ERK phosphorylation, 35S-GTPγS binding.
References:  12
Physiological Functions
GPR37 interacts with the dopamine transporter (DAT) and modulates DAT activity.
Species:  Mouse
Tissue:  Striatal presynaptic membranes
References:  11
Physiological Consequences of Altering Gene Expression
Increased expression of GPR37 in the substantia nigra pars compacta of parkin -/- lead to death of dopaminergic neurons. However, GPR37-mediated neuronal cell death can be suppressed by endoplasmic reticulum chaperone ORP150 or inhibition of dopamine synthesis, suggesting that GPR37 induces death of dopaminergic neurons in the substantia nigra pars compacta via endoplasmic reticulum stress and dopamine toxicity.
Species:  Mouse
Tissue:  Substantia nigra pars compacta
Technique:  Viral gene transfer
References:  5
Mice with GPR37 receptor knockout displayed lower striatal dopamine level.
Species:  Mouse
Tissue:  Striatum
Technique:  Gene knockouts
References:  2
Mice with GPR37 receptor knockout had an enhanced dopamine transporter (DAT)-mediated dopamine uptake activity and an increased expression of DAT. GPR-37-deficient mice also exhibited a decrease in cocaine-induced locomotor activity and in catalepsy induced by dopamine receptor antagonists.
Species:  Mouse
Tissue:  Striatal presynaptic membrane
Technique:  Gene knockouts
References:  11
Overexpression of GPR37 in cells caused unfolding of GPR37 receptors and the formation of insoluble aggregates, triggering endoplasmic reticulum-stress and eventually leading to unfolded protein-induced cell death.
Species:  Human
Tissue:  Human neuroblastoma SH-SY5Y cell line
Technique:  Gene over-expression
References:  3
GPR37-deficient mice exhibited reduced striatal dopamine content, reduced spontaneous locomotor activity and enhanced amphetamine-induced locomotor activity. GPR37-deficient mice were resistant to the neurotoxin MPTP-induced neurotoxicity, suggesting that inactivation GPR37 has protective effect on dopaminergic neurons.
Species:  Mouse
Tissue:  Brain
Technique:  Gene knockouts
References:  10
Overexpression of GPR37 receptor induced cellular autophagy.
Species:  Human
Tissue:  HEK283 cells
Technique:  Gene over-expression
References:  7
GPR37-knockout mice exhibited an increase of the basal phosphorylation of the D2-regulated Akt kinase. Additionally, GPR37-knockout mice did not respond to the the incentive properties of amphetamine or cocaine in conditioned place preference tests.
Species:  Mouse
Tissue:  Striatum
Technique:  Gene knockouts
References:  7
Mice with GPR37 knockout exhibited lower lever of endoplasmic-reticulum-associated protein degradation (ERAD) and autophagic markers.
Species:  Mouse
Tissue:  Striatum
Technique:  Gene knockouts
References:  6
GPR37 transgenic mice exhibited higher level of striatal 3,4-dihydroxyphenylacetic acid and vesicular dopamine content. The nigrostriatal dopaminergic neurons of GPR37 transgenic mice were more vulnerable to Parkinson's diseasse-related neurotoxins.
Species:  Mouse
Tissue:  Striatum, nigrostriatal dopaminergic neurons
Technique:  Gene transfer
References:  2
parkin knockout/ GPR37 transgenic mice displayed early and progressive loss of dopaminergic and noradrenergic neurons without formation of inclusion bodies, reduced tyrosine hydroxylase-immunoreactivity in the striatum, choronic and persistent activation of unfolded protein response (UPR) in the midbrain, and upregulation of CHOP, JNK2 and caspase-12 in the midbrain.
Species:  Mouse
Tissue:  Striatum, midbrain
Technique:  Crossbreading two mouse lines (transgenic mice that express human GPR37 and parkin knockout mice)
References:  17
Effects of prosaposin on ERK phosphorylation and cell survival in cortical astrocytes were abolished by siRNA knockdown of GPR37.
Species:  Mouse
Tissue:  Primary cortical astrocytes.
Technique:  siRNA knockdown.
References:  12
Physiological Consequences of Altering Gene Expression Comments
It is reported that overexpression of GPR37 led to aggregate formation, retention of the receptor in the cytoplasm and low survival rates of transfected cells [15].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Gpr37tm1.1Ryot Gpr37tm1.1Ryot/Gpr37tm1.1Ryot
involves: C57BL/6
MGI:1313297  MP:0002206 abnormal CNS synaptic transmission PMID: 17889953 
Gpr37tm1.1Ryot Gpr37tm1.1Ryot/Gpr37tm1.1Ryot
involves: C57BL/6
MGI:1313297  MP:0002945 abnormal inhibitory postsynaptic currents PMID: 17889953 
Gpr37tm2Gtva Gpr37tm2Gtva/Gpr37tm2Gtva
involves: 129P2/OlaHsd * C57BL/6J
MGI:1313297  MP:0001392 abnormal locomotor activity PMID: 15218106 
Gpr37tm1.1Ryot Gpr37tm1.1Ryot/Gpr37tm1.1Ryot
involves: C57BL/6
MGI:1313297  MP:0004811 abnormal neuron physiology PMID: 17889953 
Gpr37tm2Gtva Gpr37tm2Gtva/Gpr37tm2Gtva
involves: 129P2/OlaHsd * C57BL/6J
MGI:1313297  MP:0000836 abnormal substantia nigra morphology PMID: 15218106 
Gpr37tm2Gtva Gpr37tm2Gtva/Gpr37tm2Gtva
involves: 129P2/OlaHsd * C57BL/6J
MGI:1313297  MP:0005643 decreased dopamine level PMID: 15218106 
Gpr37tm1.1Ryot Gpr37tm1.1Ryot/Gpr37tm1.1Ryot
involves: C57BL/6
MGI:1313297  MP:0005643 decreased dopamine level PMID: 17889953 
Gpr37tm1.1Ryot Gpr37tm1.1Ryot/Gpr37tm1.1Ryot
involves: C57BL/6
MGI:1313297  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 17889953 
Gpr37tm2Gtva Gpr37tm2Gtva/Gpr37tm2Gtva
involves: 129P2/OlaHsd * C57BL/6J
MGI:1313297  MP:0001402 hypoactivity PMID: 15218106 
Gpr37tm1.1Ryot Gpr37tm1.1Ryot/Gpr37tm1.1Ryot
involves: C57BL/6
MGI:1313297  MP:0001402 hypoactivity PMID: 17889953 
Gpr37tm2Gtva Gpr37tm2Gtva/Gpr37tm2Gtva
involves: 129P2/OlaHsd * C57BL/6J
MGI:1313297  MP:0001405 impaired coordination PMID: 15218106 
Gpr37tm1Dgen Gpr37tm1Dgen/Gpr37tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1313297  MP:0005458 increased percent body fat
Gpr37tm1.1Ryot Gpr37tm1.1Ryot/Gpr37tm1.1Ryot
involves: C57BL/6
MGI:1313297  MP:0003224 neuron degeneration PMID: 17889953 
Gpr37tm1Gtva Gpr37tm1Gtva/Gpr37tm1Gtva
involves: 129P2/OlaHsd * C57BL/6J
MGI:1313297  MP:0002169 no abnormal phenotype detected PMID: 15218106 
Gene Expression and Pathophysiology Comments
GPR37 has been reported to be a substrate for the ubiquitin ligase parkin, a gene product responsible for autosomal recessive juvenile Parkinsonism and to accumulate in the brains of patients with this condition [3], as well as in Lewy bodies in the brains of adult patients with Parkinson's disease [13]. Hypermethylation of GPR37 has been found in acute myeloid leukemia [16].
General Comments
Proposed ligand (prosaposin), supported by one publication [12].

GPR37 has been reported to be a substrate for the ubiquitin ligase parkin, a gene product responsible for autosomal recessive juvenile Parkinsonism and to accumulate in the brains of patients with this condition [3].

References

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1. Bodenmüller H, Schaller HC. (1981) Conserved amino acid sequence of a neuropeptide, the head activator, from coelenterates to humans. Nature293 (5833): 579-80. [PMID:7290191]

2. Imai Y, Inoue H, Kataoka A, Hua-Qin W, Masuda M, Ikeda T, Tsukita K, Soda M, Kodama T, Fuwa T, Honda Y, Kaneko S, Matsumoto S, Wakamatsu K, Ito S, Miura M, Aosaki T, Itohara S, Takahashi R. (2007) Pael receptor is involved in dopamine metabolism in the nigrostriatal system. Neurosci. Res.59 (4): 413-25. [PMID:17889953]

3. Imai Y, Soda M, Inoue H, Hattori N, Mizuno Y, Takahashi R. (2001) An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin. Cell105 (7): 891-902. [PMID:11439185]

4. Ito J, Ito M, Nambu H, Fujikawa T, Tanaka K, Iwaasa H, Tokita S. (2009) Anatomical and histological profiling of orphan G-protein-coupled receptor expression in gastrointestinal tract of C57BL/6J mice. Cell Tissue Res.338 (2): 257-69. [PMID:19763624]

5. Kitao Y, Imai Y, Ozawa K, Kataoka A, Ikeda T, Soda M, Nakimawa K, Kiyama H, Stern DM, Hori O, Wakamatsu K, Ito S, Itohara S, Takahashi R, Ogawa S. (2007) Pael receptor induces death of dopaminergic neurons in the substantia nigra via endoplasmic reticulum stress and dopamine toxicity, which is enhanced under condition of parkin inactivation. Hum. Mol. Genet.16 (1): 50-60. [PMID:17116640]

6. Marazziti D, Di Pietro C, Golini E, Mandillo S, Matteoni R, Tocchini-Valentini GP. (2009) Induction of macroautophagy by overexpression of the Parkinson's disease-associated GPR37 receptor. FASEB J.23 (6): 1978-87. [PMID:19218498]

7. Marazziti D, Di Pietro C, Mandillo S, Golini E, Matteoni R, Tocchini-Valentini GP. (2011) Absence of the GPR37/PAEL receptor impairs striatal Akt and ERK2 phosphorylation, DeltaFosB expression, and conditioned place preference to amphetamine and cocaine. FASEB J.25 (6): 2071-81. [PMID:21372109]

8. Marazziti D, Gallo A, Golini E, Matteoni R, Tocchini-Valentini GP. (1998) Molecular cloning and chromosomal localization of the mouse Gpr37 gene encoding an orphan G-protein-coupled peptide receptor expressed in brain and testis. Genomics53 (3): 315-24. [PMID:9799598]

9. Marazziti D, Golini E, Gallo A, Lombardi MS, Matteoni R, Tocchini-Valentini GP. (1997) Cloning of GPR37, a gene located on chromosome 7 encoding a putative G-protein-coupled peptide receptor, from a human frontal brain EST library. Genomics45 (1): 68-77. [PMID:9339362]

10. Marazziti D, Golini E, Mandillo S, Magrelli A, Witke W, Matteoni R, Tocchini-Valentini GP. (2004) Altered dopamine signaling and MPTP resistance in mice lacking the Parkinson's disease-associated GPR37/parkin-associated endothelin-like receptor. Proc. Natl. Acad. Sci. U.S.A.101 (27): 10189-94. [PMID:15218106]

11. Marazziti D, Mandillo S, Di Pietro C, Golini E, Matteoni R, Tocchini-Valentini GP. (2007) GPR37 associates with the dopamine transporter to modulate dopamine uptake and behavioral responses to dopaminergic drugs. Proc. Natl. Acad. Sci. U.S.A.104 (23): 9846-51. [PMID:17519329]

12. Meyer RC, Giddens MM, Schaefer SA, Hall RA. (2013) GPR37 and GPR37L1 are receptors for the neuroprotective and glioprotective factors prosaptide and prosaposin. Proc. Natl. Acad. Sci. U.S.A.,  [Epub ahead of print]. [PMID:23690594]

13. Murakami T, Shoji M, Imai Y, Inoue H, Kawarabayashi T, Matsubara E, Harigaya Y, Sasaki A, Takahashi R, Abe K. (2004) Pael-R is accumulated in Lewy bodies of Parkinson's disease. Ann. Neurol.55 (3): 439-42. [PMID:14991825]

14. Nakahara T, Kuroki T, Ohta E, Kajihata T, Yamada H, Yamanaka M, Hashimoto K, Tsutsumi T, Hirano M, Uchimura H. (2003) Effect of the neurotoxic dose of methamphetamine on gene expression of parkin and Pael-receptors in rat striatum. Parkinsonism Relat. Disord.9 (4): 213-9. [PMID:12618056]

15. Rezgaoui M, Süsens U, Ignatov A, Gelderblom M, Glassmeier G, Franke I, Urny J, Imai Y, Takahashi R, Schaller HC. (2006) The neuropeptide head activator is a high-affinity ligand for the orphan G-protein-coupled receptor GPR37. J Cell Sci119: 542-549. [PMID:16443751]

16. Toyota M, Kopecky KJ, Toyota MO, Jair KW, Willman CL, Issa JP. (2001) Methylation profiling in acute myeloid leukemia. Blood97 (9): 2823-9. [PMID:11313277]

17. Wang HQ, Imai Y, Inoue H, Kataoka A, Iita S, Nukina N, Takahashi R. (2008) Pael-R transgenic mice crossed with parkin deficient mice displayed progressive and selective catecholaminergic neuronal loss. J. Neurochem.107 (1): 171-85. [PMID:18691389]

18. Wang J, Duhart HM, Xu Z, Patterson TA, Newport GD, Ali SF. (2008) Comparison of the time courses of selective gene expression and dopaminergic depletion induced by MPP+ in MN9D cells. Neurochem. Int.52 (6): 1037-43. [PMID:18069091]

19. Zeng Z, Su K, Kyaw H, Li Y. (1997) A novel endothelin receptor type-B-like gene enriched in the brain. Biochem. Biophys. Res. Commun.233 (2): 559-67. [PMID:9144577]

Contributors

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How to cite this page

Anthony P. Davenport, Stephen Alexander, Joanna L. Sharman, Adam J. Pawson, Helen E. Benson, Amy E. Monaghan, Wen Chiy Liew, Chido Mpamhanga, Jim Battey, Richard V. Benya, Robert T. Jensen, Sadashiva Karnik, Evi Kostenis, Eliot Spindel, Laura Storjohann, Kalyan Tirupula, Tom I. Bonner, Richard Neubig, Jean-Philippe Pin, Michael Spedding, Anthony Harmar.
Class A Orphans: GPR37. Last modified on 30/07/2015. Accessed on 24/02/2017. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=103.