Slick and Slack Heteromers in Neuronal Excitability

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DESCRIPTION (provided by applicant): KNa channels are activated by intracellular sodium and show only weak voltage dependence. The two genes which encode these channels, Slack and Slick, show overlapping mRNA and protein expression in certain brain regions, most notably in the auditory and olfactory systems. Slack and Slick channels differ significantly in their activation kinetics and their sensitivity to intracellular chloride, ATP and PKC. The specific aims of this proposal will determine whether they form heteromeric channels which contribute to native KNa currents in principal auditory neurons of the medial nucleus of the trapezoid body (MNTB). This proposal will address three specific aims. Aim 1 will determine whether Slack and Slick form heteromeric channels in heterologous expression systems. In Aim 2 we will assess the role of Slick and Slack subunits in the native KNa current of principal neurons of the MNTB. Specifically, we will test the hypothesis that Slick and Slack current levels contribute to the temporal accuracy of different patterns of action potential firing at different stimulation frequencies. Aim 3 will study the physiological significance of PKC modulation of Slack and Slick in regulating the excitability of native neurons. Experiments in this proposal will use techniques of molecular biology, electrophysiology and Na+ imaging. The purpose of this proposal is to identify the role of KNa in auditory neurons and consequently increase our understanding of auditory network properties. It is our belief that this will lead to potential, therapeutic targets for pathological conditions such as are seen when auditory hypersensitivity gates stereotypic motor autistic behavior patterns. Furthering our understanding of normal sensory encoding could have far reaching implications towards our understanding of Autism and other overlapping conditions such as Fragile X syndrome, Reft syndrome and Tuberous sclerosis complex. In addition, advancing the knowledge of this unique class of channels will in all likelihood lead to therapeutic interventions due to their putative protective roles in hypoxia and cerebral ischemia. Moreover, their pharmacological activation would make them a target for control of epileptic seizure activity.