Ion channels selectively control the flow of ions in and out of cells. The coordination of expression of various on channels is essential for maintaining appropriate patterns of excitability and accurate communication between neurons. One special class of potassium channels called sodium-activated potassium, K(Na), channels regulate the rate at which neuronal firing adapts to maintain stimulation and can protect neurons from injury during hypoxic conditions. The Slack gene encodes a K(Na) channel that is highly expressed in the central nervous system with particularly high levels of expression in olfactory cells and the auditory brainstem. The Slack gene is regulated by alternative promoters that give rise to different amino-terminal isoforms. One isoform, Slack-A, activates very rapidly in response to depolarization while the other, Slack-B, activates relatively slowly. The difference in activation kinetics of Slack subunits could determine the overall rate of adaptation of neuron. The purpose of this training proposal is to determine the genetic complexity of expression patterns of Slack channels in the CMS and how this shapes the electrical properties of native neurons. Experiments in this training proposal will use molecular, biochemical and electrophysiological techniques to examine the genetic diversity and regulation of K(Na) currents. Because K(Na) channels may protect neurons and cardiac cells from hypoxic injury, an understanding of the genetic regulation of K(Na) channels and their biological function in both normal and pathological conditions will lead to therapeutically useful treatments for cerebral ischemia and stroke. In addition, these studies could lead to a greater understanding of the pathological changes in excitability during epileptic seizures.
| Brown, Maile R; Kronengold, Jack; Gazula, Valeswara-Rao et al. (2010) Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat Neurosci 13:819-21 |
| Brown, Maile R; Kronengold, Jack; Gazula, Valeswara-Rao et al. (2008) Amino-termini isoforms of the Slack K+ channel, regulated by alternative promoters, differentially modulate rhythmic firing and adaptation. J Physiol 586:5161-79 |
