Molecular Mechanisms of Cardiac Ca2+ Channels

心脏 Ca2 通道的分子机制

• 批准号: 7220037
• 负责人: ARNOLD SCHWARTZ
• 金额: $ 37.67万
• 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/7220037
• 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

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Ca2+通道紧密耦合（EC），在每次跳动时提供所需的Ca2+进入以启动收缩。钙是在去极化和收缩之间起联系作用的阳离子。我们一直在研究包含L-VDCC的复杂结构和调控，其亚基包括alpha1C， beta和alpha2/delta，采用转基因方法而不是异种系统。通过这种方式，我们能够描绘出体内的功能。对心脏通道亚基的转基因重塑不仅是一种测定和改变体内亚基化学计量的便捷方法，而且为研究钙相关心功能障碍提供了一种模型。长期目标是表征体内调节的l电压依赖性Ca2+通道，在钙调节方面。在这篇修订后的应用中，我们强调了孔单位（即alpha1C）、β -和alpha2/delta1亚基在小鼠和人类心脏正常和心脏肥厚/衰竭中对孔单位的调节中的体内作用。敲除alpha2/delta1基因的策略应该能够提供关于正常心脏和心力衰竭中孔单位调节的重要而详细的信息。这些转基因方法应该提供关于L-VDCC如何在体内发挥作用的新信息，以及每个相关亚基如何参与孔单位的调节。希望这些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。具体目的是：转基因重塑和描述小鼠心肌中l -电压依赖性Ca2+通道亚基组成的体内作用：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)敲除α 2/ δ亚基。