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）通道构成了一个大型多样的离子通道家族，该家族涉及调节静息膜电位，动作电位波形，神经递质释放和节奏的神经元的节奏射击模式。由KV通道基因突变引起的几种遗传性人类疾病强调了它们的关键作用。在许多不同类型的KV通道中，KV3型通道具有独特的生物物理特性：非常快速的激活和失活动力学，高激活阈值和大型单位电导，使神经元在极高频率下发射狭窄动作电位的特性。在KV3型通道中，Kv3.1和Kv3.3的亚基在小脑中高度表达，而Kv3-null突变小鼠中的某些行为观察到的表型是小脑功能障碍的特征，例如运动不良，与此建议相关，与此建议相关，与此建议相关，非常高于酒精的敏感性。我们以前已经表明，小脑Purkinje细胞的发射模式改变了运动功能受损，但没有提高酒精敏感性。在这里，我们提出了实验，以检验以下假设：kv3.1/kv3.3双突变体的极端酒精敏感性源自颗粒细胞生理学的变化，通常表达高水平KV3.1和Kv3.3通道亚基的神经元。我们将使用一种分子生物学方法来将高酒精敏感性的神经元起源定位在KV3突变小鼠小脑中。在未来的工作中，这种方法将使我们能够研究脑片制剂中神经元生理的改变，并将神经元放电模式的变化与相应的行为改变相关联，特别是与酒精的醉酒作用。 公共卫生相关性：我们最近开发了对低浓度酒精非常敏感的钾通道突出小鼠。因此，这些小鼠将使用定义明确的啮齿动物模型，以研究电生理变化，即改变神经元的发射模式，从而引起极端的酒精敏感性。