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¹ Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 6530499, Chile
² Department of Biological Sciences Smith College, Northampton, MA 01063
³ Doctoral Programe, Pontificia Universidad Católica de Chile, Facultad de Ciencias Biológicas, Departamento de Ciencias Fisiológicas, Cesilla 1140, Santiago, Chile

Address correspondence to Dr. E. Jaimovich, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Casilla 70005, Santiago 6530499, Chile. Fax: (56) 2 777-6916; E-mail: ejaimovi{at}machi.med.uchile.cl

The dihydropyridine receptor (DHPR), normally a voltage-dependent calcium channel, functions in skeletal muscle essentially as a voltage sensor, triggering intracellular calcium release for excitation-contraction coupling. In addition to this fast calcium release, via ryanodine receptor (RYR) channels, depolarization of skeletal myotubes evokes slow calcium waves, unrelated to contraction, that involve the cell nucleus (Jaimovich, E., R. Reyes, J.L. Liberona, and J.A. Powell. 2000. Am. J. Physiol. Cell Physiol. 278:C998–C1010). We tested the hypothesis that DHPR may also be the voltage sensor for these slow calcium signals. In cultures of primary rat myotubes, 10 µM nifedipine (a DHPR inhibitor) completely blocked the slow calcium (fluo-3-fluorescence) transient after 47 mM K⁺ depolarization and only partially reduced the fast Ca²⁺ signal. Dysgenic myotubes from the GLT cell line, which do not express the ₁ subunit of the DHPR, did not show either type of calcium transient following depolarization. After transfection of the ₁ DNA into the GLT cells, K⁺ depolarization induced slow calcium transients that were similar to those present in normal C₂C₁₂ and normal NLT cell lines. Slow calcium transients in transfected cells were blocked by nifedipine as well as by the G protein inhibitor, pertussis toxin, but not by ryanodine, the RYR inhibitor. Since slow Ca²⁺ transients appear to be mediated by IP₃, we measured the increase of IP₃ mass after K⁺ depolarization. The IP₃ transient seen in control cells was inhibited by nifedipine and was absent in nontransfected dysgenic cells, but ₁-transfected cells recovered the depolarization-induced IP₃ transient. In normal myotubes, 10 µM nifedipine, but not ryanodine, inhibited c-jun and c-fos mRNA increase after K⁺ depolarization. These results suggest a role for DHPR-mediated calcium signals in regulation of early gene expression. A model of excitation-transcription coupling is presented in which both G proteins and IP₃ appear as important downstream mediators after sensing of depolarization by DHPR.

Key Words: dysgenic cells • gene expression • calcium waves • inositol trisphosphate • excitation transcription

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