Molecular Mechanisms of Cardiac Ca2+ Channels

心脏 Ca2 通道的分子机制

• 批准号: 7099951
• 负责人: ARNOLD SCHWARTZ
• 金额: $ 38.78万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7099951
• 关键词: calcium channel; calcium flux; cardiac myocytes; echocardiography; gene induction /repression; genetic regulation; genetically modified animals; heart contraction; heart failure; intracellular transport; laboratory mouse; molecular genetics; molecular pathology; muscle contraction; protein structure function; ventricular hypertrophy; voltage gated channel

DESCRIPTION (provided by applicant): Cardiac excitation-contraction is tightly coupled (EC) via the L-voltage-dependent Ca2+ Channel supplying the required Ca2+ ingress with each beat to initiate contraction. Calcium is the cation that serves as the link between depolarization and contraction. We have been studying the complex architecture and regulation that comprises the L-VDCC, the subunits of which include the alpha1C, beta and the alpha2/delta, employing transgenic approaches rather than heterologous systems. In this manner, we are able to delineate in vivo function. Transgenic remodeling of the channel subunits in the heart is not only a convenient way to determine and alter subunit stoichoimetry in vivo, but it provides a model for studying cardiac dysfunction related to calcium. The long-term objective is to characterize the in vivo regulation of the L-voltage-dependent Ca2+ Channel, in terms of calcium regulation. In this revised application, we emphasize the in vivo roles of the pore unit (i.e., the alpha1C), the beta- and the alpha2/delta1 subunits in regulation of the pore unit in normal and cardiac hypertrophy/failure in the mouse and human heart. A knockout strategy of the alpha2/delta1 should yield significant and detailed information on regulation of the pore unit in normal heart and possibly in heart failure. These transgenic approaches should provide new information regarding how the L-VDCC functions in vivo , and how each of the associated subunits contributes to the regulation of the pore unit. Hopefully , the data will be useful in eventually designing rational pharmacotherapeutic and genetic prevention/treatment strategies. The Specific Aims are: Transgenic remodeling of and delineating in vivo roles for subunit composition of mouse myocardium of L-voltage-dependent Ca2+ Channels: 1) Characterization of the alpha1C subunit: molecular mechanisms of cardiac hypertrophy/failure. 2) Roles of the beta-subunits; 3) Knockout of the alpha2/delta subunit.

描述（由申请人提供）：心脏兴奋-收缩通过L电压依赖性Ca 2+通道紧密耦合（EC），在每次搏动时提供所需的Ca 2+进入以启动收缩。钙离子是连接去极化和收缩的阳离子。我们一直在采用转基因方法而不是异源系统研究组成L-VDCC的复杂结构和调节，其亚基包括alpha 1C、beta和alpha 2/delta。以这种方式，我们能够描绘体内功能。转基因心脏通道亚单位的重构不仅是一种方便的方法来确定和改变体内亚单位的化学计量，但它提供了一个模型，研究心脏功能障碍与钙。长期目标是在钙调节方面表征L-电压依赖性Ca 2+通道的体内调节。在该修改的申请中，我们强调孔单元的体内作用（即，α 1 C）、β-和α 2/δ 1亚基在调节小鼠和人类心脏正常和心脏肥大/衰竭中的孔单位中的作用。α 2/δ 1的敲除策略应该产生关于正常心脏和可能的心力衰竭中的孔单元的调节的重要和详细的信息。这些转基因方法应该提供新的信息，关于L-VDCC如何在体内的功能，以及如何每个相关的亚基有助于调节的孔单位。希望这些数据将有助于最终设计合理的药物和遗传预防/治疗策略。具体目标是：L-电压依赖性Ca 2+通道小鼠心肌亚基组成的转基因重构和体内作用的描述：1）α 1C亚基的表征：心脏肥大/衰竭的分子机制。2)β亚基的作用; 3）α 2/δ亚基的敲除。