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.
