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Molecular Mechanisms of Cardiac Ca2+ Channels

心脏 Ca2 通道的分子机制

基本信息

批准号：
7585164
负责人：
ARNOLD SCHWARTZ
金额：
$ 37万
依托单位：
UNIVERSITY OF CINCINNATI
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-15 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7585164
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 Proteins Receptor Signaling Reflex action Regulation Role Seizures Signal Pathway Sleep Disorders Stress Structure-Activity Relationship Study models Surface System Techniques Therapeutic Transgenic Organisms Up-Regulation Upper arm age related blood pressure regulation density design gabapentin heart cell in vivo interest knockout animal loss of function overexpression receptor research study response trafficking treatment strategy voltage

项目摘要

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-收缩是紧密耦合（EC）通过l电压依赖性Ca2+通道供应