The structural and molecular determinants of resurgent sodium current

复苏钠电流的结构和分子决定因素

• 批准号: 8391695
• 负责人: Amanda Halley Lewis
• 金额: $ 3.49万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391695
• 关键词: Action Potentials; Address; Affinity; Ataxia; Behavior; Bioinformatics; Brain; Brain Stem; Cells; Cerebellum; Characteristics; Complex; Cytoplasmic Tail; Environment; Evolution; Fire - disasters; Goals; Ions; Kinetics; Lysine; Molecular; Molecular Conformation; Motor; Movement; Movement Disorders; Mutation; Neurons; Output; Pain Disorder; Peptides; Phenylalanine; Phosphorylation; Pilot Projects; Predisposition; Property; Protein Isoforms; Proteins; Relative (related person); Role; Series; Sodium; Staging; System; Testing; Tremor; base; bean; cell type; channel blockers; granule cell; insight; interest; motor control; novel; peptide A; public health relevance; reconstitution; research study; voltage

DESCRIPTION (provided by applicant): Voltage-gated Na channels in many neurons, including several types in the cerebellum and brainstem, are specialized to allow rapid firing of action potentials. This rapid firing is due in part to resurgent Na current, an unusual current that flows upon repolarization from positive to negative potentials. Resurgent current flows through voltage-gated Na channel 1 subunits that are recovering through open states from block by an endogenous protein. Disruption of resurgent Na current correlates with reduced firing and motor deficiencies, including ataxia and tremor, whereas Na channel mutations implicated in pain and movement disorders increase both resurgent current and firing rates. Together, these findings suggest resurgent Na current is a key determinant of neuronal output and thus, normal motor function. Previous results indicate a role for the Na channel 2 subunit Nav24 as a blocker; however, Nav24 is not sufficient to produce resurgent Na current in all cell types. In the experiments proposed here, we will further investigate the biophysical and molecular determinants of block. We will evaluate structural requirements for block by testing the ability of a series of 24- derived peptides to block channels. We will also test the properties of 1 subunits that are necessary to permit resurgent current in an expression system. Confirming the identity of potential blocking proteins and identifying the biophysical mechanisms of block will help us to further understand the connection between resurgent Na current and rapid firing that is important for control of motor behaviors.

描述（由申请人提供）：许多神经元（包括小脑和脑干中的几种类型）中的电压门控Na通道专门用于快速激发动作电位。这种快速放电部分是由于Na电流的复苏，这是一种在从正电位到负电位复极时流动的不寻常电流。复苏电流流经电压门控Na通道1亚基，这些亚基通过开放状态从内源性蛋白质的阻断中恢复。复苏Na电流的中断与减少的放电和运动缺陷相关，包括共济失调和震颤，而与疼痛和运动障碍有关的Na通道突变增加了复苏电流和放电率。总之，这些发现表明，复苏的钠电流是神经元输出的关键决定因素，因此，正常的运动功能。先前的结果表明Na通道2亚基Nav 24作为阻断剂的作用;然而，Nav 24不足以在所有细胞类型中产生复苏的Na电流。在这里提出的实验中，我们将进一步研究阻断的生物物理和分子决定因素。我们将通过测试一系列24衍生肽阻断通道的能力来评估阻断的结构要求。我们还将测试1亚基的特性，这些亚基是表达系统中允许复活电流所必需的。明确潜在阻断蛋白的身份并确定阻断的生物物理机制将有助于我们进一步理解复苏的Na电流和快速放电之间的联系，这对控制运动行为至关重要。