THE ALPHA-1C CALCIUM CHANNEL IN MUSCLE

肌肉中的 ALPHA-1C 钙通道

• 批准号: 6390575
• 负责人: PHILIP T. PALADE
• 金额: $ 32.74万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-27 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390575
• 关键词: DNA footprinting; RNase protection assay; calcium channel; dexamethasone; electrophysiology; electrostimulus; gel mobility shift assay; gene expression; immunocytochemistry; laboratory rat; microarray technology; muscle contraction; muscle function; myocardium; nucleic acid sequence; polymerase chain reaction; statistics /biometry; staurosporine; striated muscles; tissue /cell culture; transcription factor; voltage /patch clamp; western blottings

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.

描述（改编自申请人的摘要）：L 型电压门控 钙通道也称为二氢吡啶受体 (DHPR) 至关重要 用于骨骼肌和心肌的兴奋-收缩耦合。每个 这些肌肉类型表达其自己的 DHPR 同工型。的作用 心肌中的 α1C 心脏 DHPR 毫无疑问可以提供 Ca2+ 的流入也需要触发细胞内储存的 Ca2+ 释放 以便在这些商店耗尽时提供补充的方法。在 血管平滑肌 这些相同的通道是几乎所有血管的作用部位 Ca2+通道阻滞剂用于治疗高血压和 心脏病。最近，某些成人骨骼肌已被证明可以 不仅表现出 DHPR 的 alpha1S 骨骼亚型，还表现出 alpha1C 心脏亚型，尽管表达水平较低。本次资助测试 关于心脏 DHPR 在成人骨骼肌中的作用的几种假设。 要测试的假设包括补充部分耗尽的 细胞内 Ca2+ 储存，防止疲劳，并有助于关闭其他功能 基因。方法包括张力、(Ca2+)i 和电生理学测量 和基因表达的测量。结果可能会建议额外的角色 对于心脏以及许多平滑肌中的 α1C 心脏 DHPR。 这笔赠款还旨在确定类固醇激素地塞米松如何 蛋白激酶 C 抑制剂星形孢菌素和电刺激调节 肌肉中心脏 DHPR 的表达，并确定反应 所涉及的转录因子和组织特异性的元件 在基因启动子内表达。其他方法将包括 用于启动子工作的传统测定。这些结果将增强 了解这一极其重要的转录调控 治疗高血压和心脏病的药物受体 疾病。