Cav1.2 Transcript Regulation in Heart and Smooth Muscle

Cav1.2 心脏和平滑肌的转录调节

• 批准号: 6984144
• 负责人: PHILIP T. PALADE
• 金额: $ 27.29万
• 依托单位: UNIV OF ARKANSAS FOR MED SCIS
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-20 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6984144
• 关键词: Accounting; Adrenergic Agents; Affect; Binding; Blood Vessels; CREB1 gene; Cardiac; Cardiac Muscle Contraction; Cardiovascular system; Cells; Cyclic AMP; Disease; Down-Regulation; Exhibits; Exons; Family; Genetic Transcription; Goals; Grant; Heart; Histocompatibility Testing; Human; Hypertension; Intervention; Kinetics; Knowledge; L-Type Calcium Channels; Lead; Link; Mediating; Muscle Cells; Muscle function; Numbers; Pharmacologic Substance; Post-Translational Regulation; Principal Investigator; Probability; Property; Protein Kinase C; Proteins; Rate; Regulation; Response Elements; Signal Transduction; Site; Smooth Muscle; Testing; Therapeutic Uses; Tissues; Transcript; Transcription Factor AP-1; Vascular Smooth Muscle; Visceral; Xenopus oocyte; adrenergic; channel blockers; human tissue; novel; programs; promoter; research study; transcription factor

DESCRIPTION (provided by applicant): A novel first exon for the human cardiac L-type calcium channel has been discovered, bringing to three the number of transcripts found with different 5' ends, each likely regulated by its own promoter. Two of these transcripts are of critical significance, since they account for the majority of transcripts in heart and smooth muscle, respectively. This grant hypothesizes that differential expression of these two principal transcripts in heart and in vascular and visceral smooth muscle not only generates significant differences in channel activity, sensitivity to protein kinase C, and steady-state inactivation but also greater ability to separately regulate expression in the three tissue types. Adrenergic agents are known to transcriptionally upregulate and then downregulate this channel in heart, but equivalent information is lacking for smooth muscle. This grant will test three specific hypotheses: 1) that heterologous expression of the different transcripts in Xenopus oocytes and human cells results in Ca currents with different amplitude, kinetics, open probability, sensitivity to protein kinase C and steady state inactivation properties; 2) that the two principal transcripts are differentially affected in heart and smooth muscle by adrenergic agents; 3) and that there are heart-specific transcription factors that bind to response elements in the heart promoter for the channel, whereas most smooth muscle expression is driven by other transcription factors that bind to response elements in the other principal channel promoter. The results will determine how the different N-termini affect channel properties and how the different transcripts are differentially regulated in vascular smooth muscle as opposed to heart and visceral smooth muscle. They could suggest new targets for pharmaceutical intervention in disorders involving alterations in expression of L-type Ca channels, such as hypertension.

描述（由申请人提供）：已经发现了人类心脏L型钙通道的新的第一个外显子，使发现的具有不同5'末端的转录物数量达到三个，每个可能由其自己的启动子调节。其中两个转录本具有至关重要的意义，因为它们分别占心脏和平滑肌转录本的大部分。该资助假设这两种主要转录物在心脏、血管和内脏平滑肌中的差异表达不仅会在通道活性、对蛋白激酶 C 的敏感性和稳态失活方面产生显着差异，而且还具有更大的能力分别调节表达三种组织类型。众所周知，肾上腺素能药物会在心脏中转录上调然后下调该通道，但平滑肌缺乏相应的信息。这笔资助将测试三个具体假设：1）非洲爪蟾卵母细胞和人类细胞中不同转录本的异源表达导致具有不同幅度、动力学、开放概率、对蛋白激酶 C 的敏感性和稳态失活特性的 Ca 电流； 2) 肾上腺素能药物对心脏和平滑肌的两种主要转录本的影响不同； 3) 并且存在与心脏通道启动子中的反应元件结合的心脏特异性转录因子，而大多数平滑肌表达是由与其他主要通道启动子中的反应元件结合的其他转录因子驱动的。结果将确定不同的 N 末端如何影响通道特性，以及不同的转录物如何在血管平滑肌（与心脏和内脏平滑肌）中进行差异调节。他们可以为涉及 L 型 Ca 通道表达改变的疾病（如高血压）的药物干预提出新的目标。