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IP₃ receptor function and localization in myotubes: an unexplored Ca²⁺ signaling pathway in skeletal muscle

Jeanne A. Powell^1,*,, Maria Angelica Carrasco^2,*, Dany S. Adams¹, Beatrice Drouet³, Juan Rios², Marioly Müller², Manuel Estrada² and Enrique Jaimovich^2,*

¹ Department of Biological Sciences, Smith College, Northampton, MA 01063, USA
² Instituto de Ciencias Biomedicas, Facultad de Medicina, Universidad de Chile, Casilla 70005, Santiago 6530499, Chile
³ Inserm U-505, 15 rue de l’Ecole de Medecine, 75006, Paris, France
^* These authors have contributed equally to this work

Author for correspondence (e-mail: jpowell{at}smith.edu)

Accepted July 6, 2001

We present evidence for an unexplored inositol 1,4,5-trisphosphate-mediated Ca²⁺ signaling pathway in skeletal muscle. RT-PCR methods confirm expression of all three known isotypes of the inositol trisphosphate receptor in cultured rodent muscle. Confocal microscopy of cultured mouse muscle, doubly labeled for inositol receptor type 1 and proteins of known distribution, reveals that the receptors are localized to the I band of the sarcoplasmic reticulum, and this staining is continuous with staining of the nuclear envelope region. These results suggest that the receptors are positioned to mediate a slowly propagating Ca²⁺ wave that follows the fast Ca²⁺ transient upon K⁺ depolarization. This slow wave, imaged using fluo-3, resulted in an increase in nucleoplasmic Ca²⁺ lasting tens of seconds, but not contraction; the slow wave was blocked by both the inositol trisphosphate receptor inhibitor 2-aminoethoxydiphenyl borate and the phospholipase C inhibitor U-73122. To test the hypothesis that these slow Ca²⁺ signals are involved in signal cascades leading to regulation of gene expression, we assayed for early effects of K⁺ depolarization on mitogen-activated protein kinases, specifically extracellular-signal related kinases 1 and 2 and the transcription factor cAMP response element-binding protein (CREB). Within 30-60 seconds following depolarization, phosphorylation of both the kinases and CREB was evident and could be inhibited by 2-aminoethoxydiphenyl borate. These results suggest a signaling system mediated by Ca²⁺ and inositol trisphosphate that could regulate gene expression in muscle cells.

Key words: Skeletal muscle, Tissue culture, Inositol 1,4,5-trisphosphate receptors, Signal transduction, Confocal

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