Molecular Mechanisms of Cardiac Ca2+ Channels

心脏 Ca2 通道的分子机制

• 批准号: 7392398
• 负责人: ARNOLD SCHWARTZ
• 金额: $ 37万
• 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/7392398
• 关键词: Ablation; Address; Affect; Affinity; Animals; Architecture; Arrhythmia; Autonomic nervous system; Binding Sites; Biochemical; Biochemical Process; Calcineurin; Calcium; Calcium Channel; Cardiac; Cardiovascular system; Cations; Cells; Cessation of life; Complex; Coupled; Coupling; Data; Development; Disease; Exhibits; Failure; Functional disorder; Gene Expression; Gene Expression Regulation; Genetic; Goals; Heart; Heart Hypertrophy; Heart failure; Homeostasis; Human; Hypertrophy; Kinetics; Knock-out; Lead; Life; Link; Molecular; Mus; Muscle; Myocardium; Neurons; Pain; Phenotype; Physiological; Prevention; Protein Overexpression; Proteins; Receptor Signaling; Reflex action; Regulation; Role; Seizures; Signal Pathway; Sleep Disorders; Stress; Structure-Activity Relationship; Study models; Surface; System; Techniques; Therapeutic; Transcriptional Activation; Transgenic Organisms; Up-Regulation; Upper arm; age related; blood pressure regulation; density; design; gabapentin; heart cell; in vivo; interest; knockout animal; loss of function; receptor; research study; response; trafficking; voltage

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 alphalC, 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 alphalC), 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 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 alphalC subunit: molecular mechanisms of cardiac hypertrophy/failure. 2) Roles of the beta-subunits; 3) Knockout of the alpha2/delta~ subunit.

心脏兴奋-收缩通过 L 电压依赖的 Ca2+ 通道紧密耦合 (EC) 每次心跳所需的 Ca2+ 进入以启动收缩。钙是充当链接的阳离子 介于去极化和收缩之间。我们一直在研究复杂的架构和监管 包括L-VDCC，其亚基包括α1C、β和α2/δ，采用 转基因方法而不是异源系统。通过这种方式，我们能够在体内描绘出 功能。心脏通道亚基的转基因重塑不仅是一种便捷的方法 确定和改变体内亚基化学计量，但它提供了研究心脏功能障碍的模型 与钙有关。 长期目标是表征 L 电压依赖性 Ca2+ 通道的体内调节， 钙调节方面。在这个修改后的应用中，我们强调了孔单元的体内作用（即， α1C)、β-和 α2/δ1 亚基在正常和心脏中孔单元的调节中 小鼠和人类心脏肥大/衰竭。 alpha2/delta1 的淘汰策略应该会产生效果 关于正常心脏和可能的心力衰竭中孔单元调节的重要而详细的信息。 这些转基因方法应该提供有关 L-VDCC 如何在 体内，以及每个相关亚基如何有助于孔单元的调节。希望， 数据将有助于最终设计合理的药物治疗和遗传预防/治疗 策略。 具体目标是： 转基因重塑并描述亚基组成的体内作用 L-电压依赖性 Ca2+ 通道的小鼠心肌： 1) alphalC 亚基的表征： 心脏肥大/衰竭的分子机制。 2）β亚基的作用； 3）淘汰赛 α2/δ~亚基。