Cloning of the slow AHP channel

描述（由申请人提供）：许多中枢和外周神经元中动作电位后的缓慢后超极化（sAHP）是由于Ca 2+依赖性、电压非依赖性K+通道的激活。 海马CA 1区的神经元已被用作研究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着深远的影响，负责调节爆发频率的尖峰频率适应，并且对正常的整合神经传递至关重要。在CA 1神经元中，sAHP的调节是参与调节睡眠-觉醒周期、唤醒、注意力以及调节感觉处理、行为、情绪和记忆巩固的上行调节性神经递质系统的主要目标之一。最初，IsAHP通道被认为是SK，小电导Ca 2+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并证实了IsAHP通道不是SK通道的证据。此外，动力学分析的sAHP和IsAHP，表明IsAHP通道可能不直接门控的Ca 3+离子，虽然升高的细胞内Ca 2+是必不可少的激活。综上所述，现在清楚的是，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性，与生物信息学和细胞类型的表达数据，所有Kf通道基因开发的15个IsAHP通道候选人的优先级列表。我们建议使用分子生物学和电生理技术相结合的克隆慢AHP通道。 IsAHP通道是最重要和分子上最难以捉摸的通道之一。确定IsAHP通道的身份将为治疗多种中枢和外周病变（如精神分裂症、癫痫、注意力缺陷综合征和睡眠障碍）提供强有力的靶点。

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.