Molecular mechanisms of voltage-gated ion channels

超出所提供的空间。 电压门控离子通道参与神经脉冲传播、突触传递、肌肉动作电位和兴奋/收缩耦合。电压门控通道的功能异常与许多神经系统疾病有关，例如癫痫、发作性共济失调和周期性麻痹。了解这些通道的正常和病理功能可能会导致许多神经系统疾病的治疗方法的发展。 电压激活的离子通道通过细胞膜上电压的变化而激活。当细胞膜去极化时，经典的电压激活钾通道打开。这已被证明是由于一个内在的电压传感器，$4，这触发了构象变化，打开通道的向外移动。然而，4美元的运动如何与通道的打开相耦合还不清楚。最近，一类新的电压激活离子通道被克隆：超极化激活的环核苷酸门控离子通道（HCN通道）。这些通道还包含一个假定的电压传感器，4美元。令人惊讶的是，HCN通道以与电压激活的钾通道相反的极性打开;也就是说，HCN通道在膜超极化时打开。我们假设4美元也是HCN通道中的电压传感器，但4美元运动和通道开放之间的耦合涉及与电压激活钾通道不同的机制。 该项目的目的是确定4美元是否是HCN通道中的电压传感器，并将这些通道中的4美元运动与电压激活钾通道中的4美元运动进行比较和对比。将使用半胱氨酸特异性荧光探针或膜不可渗透的半胱氨酸试剂在半胱氨酸取代的通道中测量$4的移动。这些测量将用于确定4美元如何在不同的渠道中移动，并将进一步加深我们对这两类渠道的不同开放机制的理解。性能现场=

EXCEED THE SPACE PROVIDED. Voltage-gated ion channels are involved in nerve impulse propagation, synaptic transmission, muscle action potentials, and excitation/contraction coupling. Abnormal function of voltage-gated channels has been implicated in many neurological diseases, for example, epilepsy, episodic ataxia, and periodic paralyses. An understanding of the normal and pathological function of these channels could lead to the development of treatments for a number of neurological diseases. Voltage-activated ion channels are activated by changes in the voltage across the cell membrane. The classic voltage-activated potassium channels open when the membrane is depolarized. This has been shown to be due to the outward movement of an intrinsic voltage sensor, $4, which triggers the conformational changes that open the channel. However, how the movement of $4 is coupled to the opening of the channel is not understood. Recently, a new class of voltage-activated ion channels were cloned: hyperpolarization-activated cyclic nucleotide-gated ion channels (HCN channels). These channels also contain a putative voltage sensor, $4. Surprisingly, the HCN channels open with the opposite polarity from the voltage-activated potassium channels; that is, the HCN channels open when the membrane is hyperpolarized. We hypothesize that $4 is also the voltage sensor in the HCN channels, but that the coupling between $4 movement and the opening of the channel involves a different mechanism than in voltage-activated potassium channels. The aim of the proposed project is to determine whether $4 is the voltage sensor in the HCN channels and to compare and contrast the $4 movement in these channels with the $4 movement in voltage-activated potassium channels. The movement of $4 will be measured in cysteine-substituted channels using cysteine-specific fluorescent probes or membrane-impermeable cysteine reagents. These measurements will be used to determine how $4 moves in the different channels and will further our understanding of the different mechanisms of opening of these two classes of channels. PERFORMANCE SITE ========================================Section End===========================================