COBRE: UNR: MOLECULAR PHYSIOL & REGULATION OF VOLUME SENSITIVE CHLORIDE CHANNEL

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 COBRE项目1将研究心脏中容量调节阴离子通道的分子生理学和调节。Cl-通道调节的分子机制对于理解细胞如何调节其体积和理解一般离子通道蛋白的结构/功能关系是重要的问题。我们先前提出ClC-3，电压依赖性Cl-通道的ClC超家族的成员，作为负责心脏和平滑肌细胞中的天然体积调节外向整流阴离子通道（VSOAC）的分子候选者。本项目提出的实验将为研究氨基末端氨基酸的各种蛋白激酶磷酸化在两种主要ClC-3亚型调节中的作用提供新的见解，使用转基因小鼠进一步研究ClC-3与天然VSOAC之间的关系并揭示其生理作用，最后将使用分子和蛋白质组学方法来鉴定构成天然VSOAC多聚体蛋白复合物的主要组分和辅助蛋白。由于心脏Cl-通道的激活可对动作电位时程和自律性产生显著影响，并且是细胞体积稳态的关键调节剂，因此这些通道在许多心肌疾病中具有重要的临床意义，包括心律失常、心肌缺血、充血性心力衰竭和肥大。该项目具有阐明心脏和心血管系统中容量敏感性Cl-通道的正常生理和可能的病理生理作用的重要潜力。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. COBRE Project 1 will study the molecular physiology and regulation of volume-regulated anion channels in the heart. The molecular mechanism of Cl- channel regulation is an important issue for understanding how cells regulate their volume and for understanding structure/function relationships of ion channel proteins in general. We previously proposed ClC-3, a member of the ClC superfamily of voltage-dependent Cl- channels, as a molecular candidate responsible for native volume-regulated outwardly rectifying anion channels (VSOACs) in cardiac and smooth muscle cells. The experiments proposed in this project will provide new insights into the role of phosphorylation by various protein kinases of amino terminus amino acids in the regulation of the two major ClC-3 isoforms, use transgenic mice to further examine the relationship between ClC-3 and native VSOACs and reveal their physiological role, and finally will use molecular and proteomic approaches to identify the major components and accessory proteins that constitute the native VSOAC multimeric protein complex. Since the activation of cardiac Cl- channels can produce significant effects on action potential duration and automaticity, and are key regulators of cell volume homeostasis, these channels have important clinical significance for several myocardial diseases, including cardiac arrhythmias, myocardial ischemia, congestive heart failure and hypertrophy. This project has significant potential of elucidating the normal physiological and possible pathophysiological role of volume-sensitive Cl- channels in the heart and cardiovascular system.