Cancer Metastasis-Suppressing Peptide Metastin Upregulates Excitatory Synaptic Transmission in Hippocampal Dentate Granule Cells

• Published in: Journal of neurophysiology 2005-11, Vol.94 (5), p.3648-3652
• Main Authors: Arai, Amy C, Xia, Yan-Fang, Suzuki, Erika, Kessler, Markus, Civelli, Olivier, Nothacker, Hans-Peter
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; Cells, Cultured; Excitatory Postsynaptic Potentials - drug effects; Excitatory Postsynaptic Potentials - physiology; Hippocampus - drug effects; Hippocampus - physiology; Kisspeptins; MAP Kinase Signaling System - physiology; Mitogen-Activated Protein Kinases - metabolism; Proteins - pharmacology; Rats; Rats, Sprague-Dawley; Synaptic Transmission - drug effects; Synaptic Transmission - physiology; Tumor Suppressor Proteins
• ISSN: 0022-3077; 1522-1598
• DOI: 10.1152/jn.00590.2005

1 Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois; and 2 Department of Pharmacology, University of California Irvine, College of Medicine, Irvine, California Submitted 8 June 2005; accepted in final form 21 July 2005 Metastin is an antimetastatic peptide encoded by the KiSS-1 gene in cancer cells. Recent studies found that metastin is a ligand for the orphan G-protein–coupled receptor GPR54, which is highly expressed in specific brain regions such as the hypothalamus and parts of the hippocampus. This study shows that activation of GPR54 by submicromolar concentrations of metastin reversibly enhances excitatory synaptic transmission in hippocampal dentate granule cells in a mitogen-activated protein (MAP) kinase–dependent manner. Synaptic enhancement by metastin was suppressed by intracellular application of the G-protein inhibitor GDP- -S and the calcium chelator BAPTA. Analysis of miniature excitatory postsynaptic currents (mEPSCs) revealed an increase in the mean amplitude but no change in event frequency. This indicates that GPR54 and the mechanism responsible for the increase in EPSCs are postsynaptic. Metastin-induced synaptic potentiation was abolished by 50 µM PD98059 and 20 µM U0126, two inhibitors of the MAP kinases ERK1 and ERK2. The effect was also blocked by inhibitors of calcium/calmodulin-dependent kinases and tyrosine kinases. RT-PCR experiments showed that both KiSS-1 and GPR54 are expressed in the hippocampal dentate gyrus. Metastin is thus a novel endogenous factor that modulates synaptic excitability in the dentate gyrus through mechanisms involving MAP kinases, which in turn may be controlled upstream by calcium-activated kinases and tyrosine kinases. Address for reprint requests and other correspondence: A. C. Arai, Department of Pharmacology, 801 N. Rutledge St., P.O. Box 19629, Springfield, IL 62794–9629 (E-mail: aarai{at}siumed.edu )