Role of Kv3-type Potassium Channels in Alcohol Sensitivity

描述(申请人提供)：电压门控钾(Kv)通道形成了一个庞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有节奏的放电模式。由Kv通道基因突变引起的几种遗传性人类疾病突显了它们的关键作用。在许多不同类型的Kv通道中，Kv3型通道显示出独特的生物物理特性：非常快的激活和去激活动力学、高的激活阈值和大的单位电导，这些特性使神经元能够以极高的频率发出窄的动作电位。在Kv3型通道中，Kv3.1和Kv3.3的亚基在小脑中高度表达，在Kv3缺失突变小鼠中观察到的一些行为表型具有小脑功能障碍的特征，如运动能力受损，与该提议相关，非常高的酒精敏感性。我们之前已经证明，小脑浦肯野细胞放电模式的改变是运动功能受损的原因，但不是酒精敏感性增强的原因。在这里，我们提出了实验来验证这样的假设，即Kv3.1/Kv3.3双重突变体的极端酒精敏感性源于颗粒细胞生理的变化，颗粒细胞是正常表达高水平Kv3.1和Kv3.3通道亚单位的神经元。我们将使用分子生物学方法来定位Kv3突变小鼠小脑中高酒精敏感性的神经元起源。在未来的工作中，这种方法将使我们能够研究脑片制备过程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变化联系起来，特别是与酒精的醉人效应相关联。 与公共卫生相关：我们最近培育了钾通道突变小鼠，它们对低浓度的酒精非常敏感。因此，这些小鼠将作为明确的啮齿动物模型来研究导致极端酒精敏感性的电生理变化，即神经元放电模式的改变。

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.