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J. Biol. Chem., Vol. 280, Issue 3, 1771-1781, January 21, 2005

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Orexin-A-induced Ca²+ Entry

EVIDENCE FOR INVOLVEMENT OF TRPC CHANNELS AND PROTEIN KINASE C REGULATION^*

Kim P. Larsson, Hanna M. Peltonen, Genevieve Bart, Lauri M. Louhivuori, Annika Penttonen, Miia Antikainen, Jyrki P. Kukkonen, and Karl E. O. Åkerman¶

From the A. I. Virtanen Institute for Molecular Sciences, Department of Neurobiology, Laboratory of Cell Biology, University of Kuopio, P. O. Box 1627, FIN-70211 Kuopio, Finland and the Department of Neuroscience, Division of Physiology, Uppsala University, BMC, P. O. Box 572, S-75123 Uppsala, Sweden

The orexins are peptide transmitters/hormones, which exert stimulatory actions in many types of cells via the G-protein-coupled OX₁ and OX₂ receptors. Our previous results have suggested that low (subnanomolar) concentrations of orexin-A activate Ca²⁺ entry, whereas higher concentrations activate phospholipase C, Ca²⁺ release, and capacitative Ca²⁺ entry. As shown here, the Ca²⁺ response to subnanomolar orexin-A concentrations was blocked by activation of protein kinase C by using different approaches (12-O-tetradecanoylphorbol acetate, dioctanoylglycerol, and diacylglycerol kinase inhibition) and protein phosphatase inhibition by calyculin A. The Ca²⁺ response to subnanomolar orexin-A concentrations was also blocked by Mg²⁺, dextromethorphan, and tetraethylammonium. These treatments neither affected the response to high concentrations of orexin-A nor the thapsigargin-stimulated capacitative entry. The capacitative entry was instead strongly suppressed by SKF96365 An inward membrane current activated by subnanomolar concentrations of orexin-A and the currents activated upon transient expression of trpc3 channels were also sensitive to Mg²⁺, dextromethorphan, and tetraethylammonium. Responses to subnanomolar concentrations of orexin-A (Ca²⁺ elevation, inward current, and membrane depolarization) were voltage-dependent with a loss of the response around –15 mV. By using reverse transcription-PCR, mRNA for the trpc1–4 channel isoforms were detected in the CHO-hOX1-C1 cells. The expression of truncated TRPC channel isoforms, in particular trpc1 and trpc3, reduced the response to subnanomolar concentrations of orexin-A but did not affect the response to higher concentrations of orexin-A. The results suggest that activation of the OX₁ receptor leads to opening of a Ca²⁺-permeable channel, involving trpc1 and -3, which is controlled by protein kinase C.

Received for publication, June 1, 2004 , and in revised form, October 28, 2004.

^* This work was supported by European Union Contracts ERBBIO4CT960699 and QLG3-CT-2002-00826, the Academy of Finland, the Sigrid Jusélius Foundation, the Magnus Ehrnrooth Foundation, the Lars Hierta Foundation, the Göran Gustafsson Foundation, and the Novo Nordisk Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AJ566614, AJ566615 and AJ566613.

^¶ To whom correspondence should be addressed: A. I. Virtanen Institute for Molecular Sciences, Dept. of Neurobiology, Laboratory of Cell Biology, University of Kuopio, P.O. Box 1627, FIN-70211 Kuopio, Finland. E-mail: karl.okerman{at}uku.fi.

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