L-type voltage-gated calcium channels also known as dihydropyridine receptors (DHPRs) are critical for excitation-contraction coupling in both skeletal and cardiac muscle. Each of these muscle types expresses its own isoform of the DHPR. The role of the alpha1C cardiac DHPR in cardiac muscle is unquestionable to both provide the influx of Ca2+ needed to trigger Ca2+ release from intracellular stores as well as to provide a means to refill those stores when they become depleted. In vascular smooth muscle these same channels are the site of action of nearly all Ca2+ channel blockers used therapeutically in the treatment of hypertension and heart disease. Recently certain adult skeletal muscles have been shown to exhibit not only the alpha1S skeletal isoform of the DHPR, but also the alpha1C cardiac isoform, although at lower levels of expression. This grant tests several hypotheses for the role of the cardiac DHPR in adult skeletal muscle. The hypotheses to be tested include refilling of partially depleted intracellular Ca2+ stores, forestalling fatigue, and serving to turn off other genes. Methods will include tension, (Ca2+)i and electrophysiology measurements and measurements of gene expression. The results may suggest additional roles for the alpha1C cardiac DHPRs in the heart as well as in many smooth muscles. This grant also seeks to determine how the steroid hormone dexamethasone, the protein kinase C inhibitor staurosporine, and electrical stimulation regulate the expression of the cardiac DHPR in muscle, and to determine the response elements for the transcription factors involved and for tissue-specific expression within the gene promoter. Additional methods will include traditional assays used for promoter work. These results will enhance understanding of the transcriptional regulation of this extremely important receptor for therapeutic agents in the treatment of hypertension and heart disease.

R01HL063903

2000-09-27

2007-07-31