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First published online January 27, 2006
doi: 10.1242/10.1242/jcs.02766

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The neuropeptide head activator is a high-affinity ligand for the orphan G-protein-coupled receptor GPR37

¹ Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
² Klinik und Poliklinik für Neurologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
³ Institut für Angewandte Physiologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany
⁴ RIKEN Brain Science Institute, Saitama 351-0198, Japan

^* Author for correspondence (e-mail: schaller{at}zmnh.uni-hamburg.de)

Accepted 26 October 2005

The neuropeptide head activator (HA) is a mitogen for mammalian cell lines of neuronal or neuroendocrine origin. HA signalling is mediated by a G-protein-coupled receptor (GPCR). Orphan GPCRs with homology to peptide receptors were screened for HA interaction. Electrophysiological recordings in frog oocytes and in mammalian cell lines as well as Ca²⁺ mobilisation assays revealed nanomolar affinities of HA to GPR37. HA signal transduction through GPR37 was mediated by an inhibitory G protein and required Ca²⁺ influx through a channel of the transient receptor potential (TRP) family. It also required activation of Ca²⁺-dependent calmodulin kinase and phosphoinositide 3-kinase. Respective inhibitors blocked HA signalling and HA-induced mitosis in GPR37-expressing cells. HA treatment resulted in internalisation of GPR37. Overexpression of GPR37 led to aggregate formation, retention of the receptor in the cytoplasm and low survival rates of transfected cells, confirming the notion that misfolded GPR37 contributes to cell death, as observed in Parkinson's disease.

Key words: G-protein-coupled receptor, GPR37, Head activator, Pael receptor, Parkinson, Signal transduction

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