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

Journal of Cell Science 119, 542-549 (2006)
Published by The Company of Biologists 2006
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Research Article

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

Meriem Rezgaoui1, Ute Süsens1, Atanas Ignatov1, Mathias Gelderblom2, Günter Glassmeier3, Inga Franke1, Jens Urny1, Yuzuru Imai4, Ryosuke Takahashi4 and H. Chica Schaller1,*

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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