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J. Biol. Chem., Vol. 281, Issue 17, 12143-12154, April 28, 2006

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Membrane Electrical Activity Elicits Inositol 1,4,5-Trisphosphate-dependent Slow Ca²⁺ Signals through a G/Phosphatidylinositol 3-Kinase Pathway in Skeletal Myotubes^*

José M. Eltit¹, Alejandra A. García, Jorge Hidalgo, José L. Liberona, Mario Chiong, Sergio Lavandero, Edio Maldonado, and Enrique Jaimovich²

From the Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Facultades de Medicina y Ciencias Químicas y Farmacéuticas, Universidad de Chile, Independecia 1027, Santiago 7, Chile

Tetanic electrical stimulation of myotubes evokes a ryanodine receptor-related fast calcium signal, during the stimulation, followed by a phospholipase C/inositol 1,4,5-trisphosphate-dependent slow calcium signal few seconds after stimulus end. L-type calcium channels (Cav 1.1, dihydropyridine receptors) acting as voltage sensors activate an unknown signaling pathway involved in phospholipase C activation. We demonstrated that both G protein and phosphatidylinositol 3-kinase were activated by electrical stimulation, and both the inositol 1,4,5-trisphosphate rise and slow calcium signal induced by electrical stimulation were blocked by pertussis toxin, by a G scavenger peptide, and by phosphatidylinositol 3-kinase inhibitors. Immunofluorescence using anti-phosphatidylinositol 3-kinase antibodies showed a clear location in striations within the cytoplasm, consistent with a position near the I band region of the sarcomere. The time course of phosphatidylinositol 3-kinase activation, monitored in single living cells using a pleckstrin homology domain fused to green fluorescent protein, was compatible with sequential phospholipase C1 activation as confirmed by phosphorylation assays for the enzyme. Co-transfection of a dominant negative form of phosphatidylinositol 3-kinase inhibited the phosphatidylinositol 3-kinase activity as well as the slow calcium signal. We conclude that G/phosphatidylinositol 3-kinase signaling pathway is involved in phospholipase C activation and the generation of the slow calcium signal induced by tetanic stimulation. We postulate that membrane potential fluctuations in skeletal muscle cells can activate a pertussis toxin-sensitive G protein, phosphatidylinositol 3-kinase, phospholipase C pathway toward modulation of long term, activity-dependent plastic changes.

Received for publication, October 14, 2005 , and in revised form, February 3, 2006.

^* This work was supported in part by the Fondo Nacional de Investigación en Areas Prioritarias (Grant 15010006 to E. J. and S. L.) and by National Institutes of Health Fogarty International Research Collaboration Award RO3TW07053-01. 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.

¹ Holds a Ph.D. fellowship from the Comisión Nacional de Investigación Científica y Tecnológica.

² To whom correspondence should be addressed. Tel.: 562-978-6067; Fax: 562-735-3510; E-mail: ejaimovi{at}med.uchile.cl.

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