This application proposes to examine the characteristics and functional significance of sodium-activated potassium channels (IK(Na)) in vertebrate central and peripheral neurons. Preliminary results indicate that this current plays a major role in determining the voltage-dependent electrical behavior of cells where it is present. The experiments described below will examine the following questions: First, what are the kinetic properties of IK(Na), and are these determined by the time course of sodium influx, the intrinsic properties of the channels themselves, or both? These experiments will utilize whole-cell and inside-out patch clamp recordings from isolated chick midbrain neurons and ciliary ganglion neurons. Second, what are the pharmacological properties of IK(Na)? These experiments will examine the effects of several known potassium-channel blocking agents, using whole- cell recordings from isolated chick neurons. These results will allow comparison of IK(Na) with other potassium currents described previously. In addition, these experiments may contribute to an understanding of the precise role of IK(Na) in regulating voltage- dependent electrical behavior in excitable cells. Third, the role of IK(Na) in modulating responses to certain neurotransmitters will be examined by means of whole-cell recordings from isolated chick neurons. These experiments will indicate the extent to which IK(Na) contributes to the process of synaptic transmission. Finally, the distribution of IK(Na) will be examined by means of whole-cell recordings from neurons isolated from several regions of the chick central and peripheral nervous systems. These experiments will determine whether IK(Na) is a widespread ionic conductance and also whether its properties are uniform in all cells where it is present. Insofar as IK(Na) is a fundamental mechanism for regulating the electrical behavior of excitable cells, these results could be applicable to a wide variety of disease states. However, the results should be especially applicable to diseases such aa epilepsy, where the normal mechanisms for regulating the electrical behavior of neurons, and especially of repetitive firing, appear to be abnormal.
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