A large array of K+ channels gives rise to a diverse population of currents. Some of the distinguishing features of channel isoforms may reside in their ability to be localized to discrete regions within a cell and to be modulated by particular second messengers. This proposal will examine two systems to investigate these issues. In myelinating Schwann cells, K+ channels are localized near the node of Ranvier. This project will determine which channels are expressed in these cells and how they are distributed. It will determine whether closely related channels that coassemble in heterologous expression systems also coassemble in their normal milieu. Transgenic mice will be used to ask whether regions of the channel molecules can be found that determine their destinations within the Schwann cell. This approach will also probe the physiological role of K+ channels in Schwann cells. In Xenopus oocytes, K+ channel genes have been screened for effects of arachidonic acid and its related compounds. A strong inhibitory effect distinguished members of the Shal family of rapidly inactivating channels. This proposal will characterize the biophysical and pharmacological properties of this modulation and will look for regions of the channel that are required for the effect. The proposal will test the hypothesis that this action is the basis of the alpha1-adrenergic reduction of the transient outward current in the heart. K+ channels are, of course, essential for proper functioning of the nervous system, heart, and many other tissues and are an important therapeutic target. This project will examine fundamental issues of K+ channel structure and function. It will also illuminate their particular functions in Schwann cells and cardiac myocytes and may therefore advance our understanding of the pathology of demyelinating diseases and cardiac arrhythmias.
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