Role of Kv3-type Potassium Channels in Alcohol Sensitivity

Kv3 型钾通道在酒精敏感性中的作用

• 批准号: 7926899
• 负责人: Jane E Johnson
• 金额: $ 23.55万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-05 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926899
• 关键词: Action Potentials; Alcohols; Animal Behavior; Applications Grants; Area; Ataxia; Behavior; Behavioral; Biological; Brain; Brain region; Cell physiology; Cells; Cerebellar Diseases; Cerebellum; Characteristics; Electroencephalography; Electrophysiology (science); Family; Feedback; Fire - disasters; Frequencies; Future; Genes; Golgi Apparatus; Hyperactive behavior; Inherited; Ion Channel; Kinetics; Knockout Mice; Letters; Mediating; Membrane Potentials; Molecular; Motor; Movement; Mus; Mutant Strains Mice; Myoclonus; Neurons; Pattern; Performance; Phenotype; Physiological; Physiology; Potassium; Potassium Channel; Predisposition; Preparation; Property; Purkinje Cells; Research Proposals; Rest; Rodent Model; Role; Sleep; Slice; Slow-Wave Sleep; System; Testing; Tetracyclines; Time; Transcription Coactivator; Tremor; Wild Type Mouse; Work; alcohol effect; alcohol sensitivity; behavior test; disease-causing mutation; granule cell; human disease; mutant; neuronal excitability; neurotransmitter release; null mutation; public health relevance; research study; restoration; voltage

DESCRIPTION (provided by applicant): Voltage-gated potassium (Kv) channels form a large and diverse family of ion channels that are involved in regulating the resting membrane potential, the action potential waveform, neurotransmitter release and rhythmic firing patterns of neurons. Their pivotal role is highlighted by several inherited human diseases caused by mutations in Kv channel genes. Among the many different types of Kv channels, Kv3-type channels display unique biophysical properties: very rapid activation and deactivation kinetics, high thresholds of activation and large unit conductances, properties that enable neurons to fire narrow actions potentials at extremely high frequencies. Among Kv3-type channels, subunits for Kv3.1 and Kv3.3 are highly expressed in the cerebellum, and some of the behaviorally observed phenotypes in Kv3-null mutant mice are characteristic of cerebellar dysfunction such as impaired motor performance and, of relevance to this proposal, very high alcohol sensitivity. We have previously shown that altered firing patterns of cerebellar Purkinje cells are responsible for impaired motor function yet not for heightened alcohol sensitivity. Here, we propose experiments to test the hypothesis that the extreme alcohol sensitivity of Kv3.1/Kv3.3-double mutants originates from changes in granule cell physiology, neurons that normally express high levels of Kv3.1 and Kv3.3 channel subunits. We will use a molecular biological approach to localize the neuronal origin of high alcohol sensitivity in the cerebellum of Kv3-mutant mice. In future work, this approach will enable us to study the altered neuronal physiology in brain-slice preparations and to correlate changes in neuronal firing patterns with the corresponding behavioral alterations, in particular with the intoxicating effects of alcohol. PUBLIC HEALTH RELEVANCE: We have recently developed potassium channel-mutant mice that are very sensitive to low concentrations of alcohol. Hence, these mice will serve as well-defined rodent models to study the electrophysiological changes, i.e., altered neuronal firing patterns, that cause extreme alcohol sensitivity.

描述（由申请人提供）：电压门控钾（Kv）通道形成了一个大而多样的离子通道家族，参与调节静息膜电位、动作电位波形、神经递质释放和神经元的节律性放电模式。它们的关键作用在由Kv通道基因突变引起的几种遗传性人类疾病中得到了强调。在许多不同类型的Kv通道中，Kv 3型通道显示出独特的生物物理特性：非常快速的激活和失活动力学，高激活阈值和大单位电导，使神经元能够以极高频率激发窄动作电位的特性。在Kv 3型通道中，Kv3.1和Kv3.3的亚基在小脑中高度表达，并且在Kv 3无效突变小鼠中观察到的一些行为表型是小脑功能障碍的特征，例如运动性能受损，并且与该提议相关，非常高的酒精敏感性。我们以前已经表明，小脑浦肯野细胞的放电模式改变是导致运动功能受损的原因，但不是导致酒精敏感性升高的原因。在这里，我们提出的实验来测试的假设，即极端的酒精敏感性Kv3.1/Kv3.3双突变体起源于颗粒细胞生理学的变化，神经元，通常表达高水平的Kv3.1和Kv3.3通道亚基。我们将使用分子生物学的方法来本地化的神经元起源的高酒精敏感性在小脑的Kv 3突变小鼠。在未来的工作中，这种方法将使我们能够研究脑切片制备中改变的神经元生理学，并将神经元放电模式的变化与相应的行为改变相关联，特别是与酒精的致醉作用相关联。 公共卫生相关性：我们最近开发了钾通道突变小鼠，它们对低浓度酒精非常敏感。因此，这些小鼠将作为明确定义的啮齿动物模型来研究电生理学变化，即，神经元放电模式的改变会导致极度酒精敏感