Cloning of the slow AHP channel

描述(申请人提供)：在许多中枢和外周神经元中，动作电位后的慢后超极化(SAHP)是由于钙离子依赖、电压非依赖的K+通道的激活所致。 海马区CA1区的神经元被用作研究SAHP和潜在电流IsAHP的模型。过去二十年的研究结果表明，SAHP对神经元的兴奋性有深远的影响，负责调节猝发频率的尖峰频率适应，对正常的、综合的神经传递是必不可少的。在CA1神经元中，SAHP的调节是上行调节性神经递质系统的主要靶点之一，该系统参与调节睡眠-觉醒周期、觉醒、注意力以及调节感觉处理、行为、情绪和记忆巩固。最初，IsAHP通道被认为是SK(小电导钙激活的K+通道)家族的成员，但最近来自SK转基因小鼠的数据巩固和证实了IsAHP通道不是SK通道的证据。此外，SAHP和IsAHP的动力学分析表明，IsAHP通道可能不被Ca3+直接门控，尽管细胞内钙离子的升高是激活IsAHP通道的必要条件。综上所述，现在很清楚的是，SAHP通道的分子身份仍然未知。我们比较了克隆通道的功能特征，结合生物信息学和所有KF通道基因的细胞类型表达数据，制定了15个IsAHP通道候选的优先列表。我们建议结合分子生物学和电生理技术来克隆慢速AHP通道。 IsAHP通道是最重要和分子上难以捉摸的通道之一。确定IsAHP通道的身份将为多种中枢和外周疾病的治疗方法提供一个强大的靶点，如精神分裂症、癫痫、注意力缺陷综合征和睡眠障碍。

DESCRIPTION (provided by applicant): The slow afterhyperpolarization (sAHP) that follows an action potential in many central and peripheral neurons is due to the activation of Ca2+-dependent, voltage-independent K+ channels. Neurons in the CA1 region of the hippocampus have served as models for studying the sAHP and the underlying currents, the IsAHP. The results of studies performed over the past two decades show that the sAHP has a profound influence on neuronal excitability, being responsible for spike-frequency adaptation that regulates burst frequency and is essential for normal, integrative neurotransmission. In CA1 neurons, regulation of the sAHP is one of the principal targets for the ascending modulatory neurotransmitter systems that are involved in regulating the sleep-wake cycle, arousal, attention, and in modulating sensory processing, behaviors, emotions and memory consolidation. Initially, the IsAHP channels were thought to be members of the SK, small conductance Ca2+-activated K+ channel family, but recent data from SK transgenic mice consolidate and confirm the evidence that the IsAHP channels are not SK channels. Moreover, kinetic analysis of the sAHP and the IsAHP, indicate that the IsAHP channels may not be directly gated by Ca3+ ions, although elevated intracellular Ca2+ is essential for their activation. Taken together, it is now clear that the molecular identities of the sAHP channels remain unknown. We have compared the functional characteristics of cloned channels in concert with bioinformatics and cell-type expression data for all Kf channel genes to develop a priority list of 15 IsAHP channel candidates. We propose to use a combination of molecular biological and electrophysiological techniques to clone the slow AHP channel. The IsAHP channels are one of the most important and molecularly elusive channels. Determining the identities of the IsAHP channels will provide a powerful target for therapeutic approaches to multiple central and peripheral pathologies such as schizophrenia, epilepsy, attention deficit syndrome, and sleep disorders.