The neuropeptide head activator is a high-affinity ligand for the orphan G-protein-coupled receptor GPR37.
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 Ca(2+) mobilisation assays revealed nanomolar affinities of HA to GPR37. HA signal transduction through GPR37 was mediated by an inhibitory G protein and required Ca(2+) influx through a channel of the transient receptor potential (TRP) family. It also required activation of Ca(2+)-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.
Rezgaoui
Meriem
M
Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Süsens
Ute
U
Ignatov
Atanas
A
Gelderblom
Mathias
M
Glassmeier
Günter
G
Franke
Inga
I
Urny
Jens
J
Imai
Yuzuru
Y
Takahashi
Ryosuke
R
Schaller
H Chica
HC
D000818:Animals; D019556:COS Cells; D002118:Calcium; D020013:Calcium Signaling / Q000187:drug effects* / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D002522:Chlorocebus aethiops; D006801:Humans; D008934:Mitogens / Q000494:pharmacology*; D009479:Neuropeptides / Q000494:pharmacology*; D009865:Oocytes / Q000166:cytology / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D014162:Transfection / Q000379:methods; D014982:Xenopus laevis / Q000378:metabolism
D002118:Calcium; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D008934:Mitogens; D009479:Neuropeptides; D019869:Phosphatidylinositol 3-Kinases; D011761:Pyrrolidonecarboxylic Acid; D043562:Receptors, G-Protein-Coupled; C480827:GPR37 receptor, human; C032522:head activator peptide