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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Balshaw, David M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Medical Br Galveston
Schools of Medicine
United States
Zip Code
Wang, Wenze; Pang, Li; Palade, Philip (2011) Angiotensin II upregulates Ca(V)1.2 protein expression in cultured arteries via endothelial H(2)O(2) production. J Vasc Res 48:67-78
Rhee, Sung W; Stimers, Joseph R; Wang, Wenze et al. (2009) Vascular smooth muscle-specific knockdown of the noncardiac form of the L-type calcium channel by microRNA-based short hairpin RNA as a potential antihypertensive therapy. J Pharmacol Exp Ther 329:775-82
Wang, Wen-Ze; Pang, Li; Palade, Philip (2008) Angiotensin II causes endothelial-dependent increase in expression of Ca(V)1.2 protein in cultured arteries. Eur J Pharmacol 599:117-20
Germinario, Elena; Esposito, Alessandra; Midrio, Menotti et al. (2008) High-frequency fatigue of skeletal muscle: role of extracellular Ca(2+). Eur J Appl Physiol 104:445-53
Esposito, Alessandra; Germinario, Elena; Zanin, Marika et al. (2007) Isoform switching in myofibrillar and excitation-contraction coupling proteins contributes to diminished contractile function in regenerating rat soleus muscle. J Appl Physiol 102:1640-8
Wang, Wen-Ze; Saada, Nehad; Dai, Bosong et al. (2006) Vascular-specific increase in exon 1B-encoded CAV1.2 channels in spontaneously hypertensive rats. Am J Hypertens 19:823-31
Sonkusare, Swapnil; Palade, Philip T; Marsh, James D et al. (2006) Vascular calcium channels and high blood pressure: pathophysiology and therapeutic implications. Vascul Pharmacol 44:131-42
Raffaello, Anna; Laveder, Paolo; Romualdi, Chiara et al. (2006) Denervation in murine fast-twitch muscle: short-term physiological changes and temporal expression profiling. Physiol Genomics 25:60-74
Danieli-Betto, Daniela; Germinario, Elena; Esposito, Alessandra et al. (2005) Sphingosine 1-phosphate protects mouse extensor digitorum longus skeletal muscle during fatigue. Am J Physiol Cell Physiol 288:C1367-73
Sandona, Dorianna; Danieli-Betto, Daniela; Germinario, Elena et al. (2005) The T-tubule membrane ATP-operated P2X4 receptor influences contractility of skeletal muscle. FASEB J 19:1184-6

Showing the most recent 10 out of 22 publications