Molecular determinants of voltage-dependent gating in T-type calcium channels

T型钙通道电压依赖性门控的分子决定因素

• 批准号: 262048-2012
• 负责人: Parent, Lucie
• 金额: $ 2.48万
• 依托单位: Université de Montréal
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2013
• 资助国家: 加拿大
• 起止时间: 2013-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=525474
• 关键词: Molecular; determinants; voltage; dependent; gating

The nerve cell, or neuron, is the key player in the activity of the nervous system. It conveys information both electrically and chemically. The mechanism underlying signal transmission within neurons is based on voltage differences that exist between the inside and the outside of the cell. This membrane potential is created by the uneven distribution of electrically charged particles, or ions, such as sodium (Na), potassium (K), chloride (Cl), and calcium (Ca). These ions enter and exit the cell through specific protein channels (ion channels) in the cell's membrane. The channels "open" or "close" in response to changes in the cell's membrane potential. The resulting redistribution of electric charges may alter the voltage difference across the membrane. A decrease in the voltage difference is called depolarization. If depolarization exceeds a certain threshold, an impulse (i.e., action potential) will travel along the neuron. The depolarization causes Ca to enter the cell through calcium channels. Hence calcium channels play an important role in neurotransmission. Over the last 20 years, three (3) different families of calcium channel proteins have been identified and characterized based upon their pharmacological, genetic and voltage sensitivities. The T-type (CaV3) channels are atypical channels that open and close much more rapidly than CaV1 and CaV2 channels. We know relatively little about the molecular mechanisms underlying these differences. We propose to identify the molecular and cellular elements controlling the rate at which T-type calcium channels open and close in response to membrane potential. An array of molecular, biochemical, and cellular techniques will be used to answer these questions. The function of mutant channels will be studied using electrophysiological and protein chemistry techniques. The behavior of the mutants will then be analyzed by computer modeling to simulate by computer the channel structure. This knowledge will provide valuable insight into future pharmacological therapies such as improved calcium channel blockers.

神经细胞或神经元是神经系统活动的关键参与者。它以电气和化学方式传递信息。神经元内信号传输的机制基于细胞内部和外部之间存在的电压差。这种膜电位是由带电粒子或离子（例如钠 (Na)、钾 (K)、氯 (Cl) 和钙 (Ca)）的不均匀分布产生的。这些离子通过细胞膜上的特定蛋白质通道（离子通道）进入和离开细胞。通道响应细胞膜电位的变化而“打开”或“关闭”。由此产生的电荷重新分布可能会改变膜上的电压差。电压差的减小称为去极化。如果去极化超过某个阈值，脉冲（即动作电位）将沿着神经元传播。去极化导致 Ca 通过钙通道进入细胞。因此，钙通道在神经传递中起着重要作用。在过去 20 年中，三 (3) 个不同的钙通道蛋白家族已根据其药理学、遗传和电压敏感性得到鉴定和表征。 T 型 (CaV3) 通道是非典型通道，其打开和关闭速度比 CaV1 和 CaV2 通道快得多。我们对这些差异背后的分子机制知之甚少。我们建议确定控制 T 型钙通道响应膜电位打开和关闭的速率的分子和细胞元件。一系列分子、生物化学和细胞技术将被用来回答这些问题。将使用电生理学和蛋白质化学技术来研究突变通道的功能。然后通过计算机建模来分析突变体的行为，以通过计算机模拟通道结构。这些知识将为未来的药物治疗（例如改进的钙通道阻滞剂）提供有价值的见解。