Involvement of shaker-like potassium channels in control of nervous system hyperexcitability
Mutations at the Drosophila Shaker locus cause motor hyperexcitability in flies, and allowed the cloning of the first voltage-gated potassium channel gene. Subsequently, at least sixteen different related potassium channel genes have been identified in each of rat, mouse, and human species. The family of voltage-gated potassium channels has been implicated in a variety of functions in the CNS, serving to limit excitability at both cellular and whole nervous system levels. Here, we present an investigation of two specific aspects of potassium channel modulation of nervous system hyperexcitability. First, we addressed the role of the widely-distributed Shaker-like channel Kv1.1 in maintenance of normal neuronal function. We have disrupted the Kcna1 gene locus in the mouse, thereby deleting the entire open reading frame of the Kv1.1 gene. Homozygous Kv1.1-null animals display frequent spontaneous seizures, alterations in nerve conduction, and changes in excitability of the hippocampal CA3 pyramidal cell population. These observations confirm the importance of this delayed rectifier potassium channel in stabilization of neuronal activity, and the surprisingly limited ability of other potassium channels to compensate for its absence. Second, we addressed the role of voltage-gated potassium channels in astrocytes, a cell type thought to be involved in buffering of extracellular potassium in the CNS to prevent neuronal hyperexcitability. As an initial step, we identified expression of a specific channel, Kv1.6, in mouse cortical astrocytes. Kv1.6 appears to underly a portion of the sustained outward potassium current in these cells. We then used a dominant negative channel subunit under control of the GFAP promoter in an attempt to ablate the function of Kv1.6 and any related Shaker-like channels in astrocytes of transgenic mice. Astrocytes in these transgenic animals appear to express the dominant negative construct, yet no abnormalities at whole animal or cellular levels have been identified.
- Pharmacology