THE ALPHA-1C CALCIUM CHANNEL IN MUSCLE

肌肉中的 ALPHA-1C 钙通道

• 批准号: 6630380
• 负责人: PHILIP T. PALADE
• 金额: $ 31.31万
• 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/6630380
• 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）是关键的 用于骨骼肌和心脏肌肉中的激发反应耦合。每个 这些肌肉类型表达了自己的DHPR同工型。角色 心脏肌肉中的α1c心脏DHPR毫无疑问地提供 还需要触发Ca2+​​从细胞内存储中释放的Ca2+涌入 为了提供这些商店耗尽时补充这些商店的手段。在 血管平滑肌这些相同的通道几乎是所有的作用部位 CA2+通道阻滞剂用于治疗高血压和 心脏病。最近，某些成年骨骼肌已被证明 不仅展示了DHPR的α1s骨骼同工型，还展示alpha1c 心脏同工型，尽管表达水平较低。此赠款测试 心脏DHPR在成人骨骼肌中的作用的几个假设。 要测试的假设包括部分耗尽的补充 细胞内Ca2+存储，防止疲劳，并关闭其他 基因。方法将包括张力，（CA2+）I和电生理测量值 和基因表达的测量。结果可能表明其他角色 对于心脏以及许多平滑肌肉的α1C心脏DHPR。 该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 心脏DHPR在肌肉中的表达，并确定反应 涉及的转录因子和组织特异性的元素 基因启动子中的表达。其他方法将包括 用于发起人工作的传统测定法。这些结果将增强 理解这一极为重要的转录调节 治疗高血压和心脏治疗剂的受体 疾病。