MOLECULAR MECHANISMS OF POTASSIUM CHANNEL FUNCTION

电压依赖性和钙依赖性钾通道是关键 细胞膜兴奋性和信号传导的控制中的分子元件 神经系统。 它们在心脏的起搏活动中起着关键作用， 内源性活跃的神经元，并在突触的调制中是重要的。 功能 钾通道已被证明在心肌细胞的凋亡中起核心作用。 在许多系统中控制和调制发射器释放。 Shaker突触前终末钾通道的改变 果蝇突变体导致动作电位复极延迟， 神经肌肉接头处的过度兴奋。 这些影响构成了 变种人档案中的行为缺陷 在亚洲， 钾通道的神经递质已被证明加强 参与敏化和联想学习的突触。 详细 了解钾通道功能的分子机制 将提供正常和病理突触功能的见解， 以及突触内可塑性。 此外， 渠道功能知识应提供更好的框架， 设计用于涉及细胞的病理状况的治疗剂 信号传导过程。 我们建议继续研究 Shaker钾通道的失活。 我们之前的工作 建立了快速灭活的“球链”机制， 包括通过氨基末端阻断通道的内口 Shaker多肽的结构域。 上次赠款期间取得的进展 这一时期已经导致了对特定氨基的作用的详细了解， 失活机制中氨基末端结构域中的酸，以及 已经定义了结合位点的一般生物物理特性， 海峡口。 下一个供资期的一个主要目标是 以确定对失活“受体位点”起作用的氨基酸。 其他实验室和我们之前的工作涉及三个区域， 受体位点的潜在部分。 我们将使用嵌合通道， 我们的N-末端肽范围，以研究这些和其他区域， 细节，以更好地了解受体的性质 位点及其与N-末端失活结构域的相互作用。 与 大电导钙激活钾克隆研究进展 电压和钙离子通道的分子机制研究 这些重要信道中的相关门控现在是可行的。 这些 通道为此类研究提供了几个优势，使其成为 研究通道门控机制的重要工具。 我们将 继续研究这些渠道的门控， 了解钙离子和电压依赖性 门控

Voltage-dependent and Calcium-dependent potassium channels are key molecular elements in the control of membrane excitability and signaling in athe nervous system. They play critical roles in the pacemaker activity of endogenously active neurons and are important in the modulation of synaptic function. Potassium channels have been shown to play a central role in the control and modulation of transmitter release in a number of systems. Alterations in potassium channels in presynaptic terminals of Shaker Drosophila mutants leads to delayed action potential repolarization and hyperexcitability at the neuromuscular junction. These effects underlie the behavioral defects in the mutant files. In Aplysia, modulation of potassium channels by neurotransmitters has been shown to strengthen synapses involved in sensitization and associative learning. A detailed understanding of the molecular mechanisms of potassium channel function will provide insights into normal and pathological synaptic function as well as intro synaptic plasticity. In addition, the advances in the knowledge of channel function should provide a better framework for designing therapeutic agents for pathological conditions involving cellular signal transduction processes. We propose to continue the study of inactivation of Shaker potassium channels. Our previous work has established a "Ball and Chain" mechanism for rapid inactivation that involves block of the internal mouth of the channel by an amino-terminal domain of the Shaker polypeptide. Progress made during the previous grant period has led to a detailed understanding of the role of specific amino acids in the amino-terminal domain in the mechanism of inactivation, and have defined the general biophysical properties of the binding site on the mouth of the channel. A major goal during the next funding period will be to define the amino-acid contributors to the inactivation "receptor site". previous work by other labs and ours has implicated three regions as potential parts of the receptor site. We will use chimeric channels and our range of N-terminal peptides to study these and other regions in more detail to get a better understanding of the properties of the receptor sites and its interaction with the N-terminal inactivation domain. With the recent cloning of large-conductance Calcium-activated potassium channels, studies of the molecular mechanisms of voltage and calcium dependent gating in these important channels are now feasible. These channels offer several advantages for such studies that make them an important tool for the study of channel gating mechanisms.. We will continue our studies of gating in these channels with a direction towards understanding the interactions between calcium and voltage-dependent gating.