This Article Full Text Full Text (PDF) All Versions of this Article: 20/1/80    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ammoun, S. Articles by Kukkonen, J. P. Search for Related Content PubMed PubMed Citation Articles by Ammoun, S. Articles by Kukkonen, J. P.

OX₁ Orexin Receptors Activate Extracellular Signal-Regulated Kinase in Chinese Hamster Ovary Cells via Multiple Mechanisms: The Role of Ca²⁺ Influx in OX₁ Receptor Signaling

The Department of Neuroscience (S.A., L.J., M.E.E., T.H., A.S.D., K.E.O.Å., J.P.K.), Unit of Physiology, Uppsala University, Biomedical Center (BMC), SE-75123 Uppsala, Sweden; the Department of Neuroscience (L.K.), Unit of Neurobiology, Uppsala University, BMC, SE-75123 Uppsala, Sweden, and Minerva Foundation Institute for Medical Research, Helsinki, Finland; Department of Neurophysiology (O.A.S., H.L.H.), Heinrich-Heine-Universität, D-40001 Düsseldorf, Germany; and the A. I. Virtanen Institute for Molecular Sciences (K.E.O.Å.), University of Kuopio, Neulaniementie 2, FIN-70210 Kuopio, Finland

Address all correspondence and requests for reprints to: Jyrki P. Kukkonen, Department of Neuroscience, Division of Physiology, Uppsala University, BMC, P.O. Box 572, SE-75123 Uppsala, Sweden. E-mail: jyrki.kukkonen{at}neuro.uu.se.

Activation of OX₁ orexin receptors heterologously expressed in Chinese hamster ovary (CHO) cells led to a rapid, strong, and long-lasting increase in ERK phosphorylation (activation). Dissection of the signal pathways to ERK using multiple inhibitors and dominant-negative constructs indicated involvement of Ras, protein kinase C, phosphoinositide-3-kinase, and Src. Most interestingly, Ca²⁺ influx appeared central for the ERK response in CHO cells, and the same was indicated in recombinant neuro-2a cells and cultured rat striatal neurons. Detailed investigations in CHO cells showed that inhibition of the receptor- and store-operated Ca²⁺ influx pathways could fully attenuate the response, whereas inhibition of the store-operated Ca²⁺ influx pathway alone or the Ca²⁺ release was ineffective. If the receptor-operated pathway was blocked, an exogenously activated store-operated pathway could take its place and restore the coupling of OX₁ receptors to ERK. Further experiments suggested that Ca²⁺ influx, as such, may not be required for ERK phosphorylation, but that Ca²⁺, elevated via influx, acts as a switch enabling OX₁ receptors to couple to cascades leading to ERK phosphorylation, cAMP elevation, and phospholipase C activation. In conclusion, the data suggest that the primary coupling of orexin receptors to Ca²⁺ influx allows them to couple to other signal pathways; in the absence of coupling to Ca²⁺ influx, orexin receptors can act as signal integrators by taking advantage of other Ca²⁺ influx pathways.

This article has been cited by other articles:

				S. Ammoun, D. Lindholm, H. Wootz, K. E. O. Akerman, and J. P. Kukkonen G-protein-coupled OX1 Orexin/hcrtr-1 Hypocretin Receptors Induce Caspase-dependent and -independent Cell Death through p38 Mitogen-/Stress-activated Protein Kinase J. Biol. Chem., January 13, 2006; 281(2): 834 - 842. [Abstract] [Full Text] [PDF]