THE ALPHA-1C CALCIUM CHANNEL IN MUSCLE

描述（改编自申请人摘要）：L型电压门控 钙通道也称为二氢吡啶受体（DHPR）， 用于骨骼肌和心肌的兴奋-收缩偶联。每个 这些肌肉类型表达其自身的DHPR同种型。的作用 心肌中的α 1C心脏DHPR无疑提供了 也需要Ca 2+内流来触发细胞内钙库的Ca 2+释放 以提供在这些储备耗尽时再填充这些储备的手段。在 血管平滑肌这些相同的渠道是网站的行动几乎所有 用于治疗高血压的Ca 2+通道阻断剂， 心脏病最近，某些成人骨骼肌已被证明 不仅表现出DHPR的α 1 S骨架亚型，而且还表现出α 1C骨架亚型。 心脏同种型，尽管表达水平较低。这批测试 心脏DHPR在成人骨骼肌中的作用的几种假设。 要检验的假设包括部分枯竭的 细胞内Ca 2+储存，预防疲劳，并关闭其他 基因.方法包括张力、（Ca 2+）i和电生理学测量 和基因表达的测量。这些结果可能表明， 心脏和许多平滑肌中的α 1C心脏DHPR。 这项拨款还旨在确定类固醇激素地塞米松， 蛋白激酶C抑制剂staurosporine和电刺激调节 心脏DHPR在肌肉中的表达，并确定反应 所涉及的转录因子和组织特异性转录因子的元件 在基因启动子内表达。其他方法包括 用于启动子工作的传统测定法。这些结果将增强 理解这一极其重要的转录调控 用于治疗高血压和心脏病的治疗剂的受体 疾病

DESCRIPTION (Adapted from the applicant's abstract): 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.