K+ channels are essential for nerve, muscle, endocrine, and immune cells. An understanding of these channels is vital for understanding the basic properties of electrically excitable cells and for understanding the manner in which those properties are varied to give a cell its individual character. The regulation of K+ channels has been shown to be a mechanism by which the plasticity underlying simple forms of learning can take place. The biochemical study of these channels has recently been facilitated by the cloning of the Shaker locus of Drosophila melanogaster. This gene, through alternative splicing of mRNA, gives rise to a family of proteins that can form K+ channels of the type known as A-channels. This application proposes a continuation of that research and will be directed to two questions about the Shaker products. 1) How are different subtypes of a channel distributed within an organism and within a single neuron in order to produce the appropriate physiological properties of a cell? Antibodies to common regions and to sequences that characterize particular splicing variants will be used for immunocytochemistry. Do these variants have s differential tissue distribution? Are variants targeted to particular subcellular locations such as terminals, axons, or post-synaptic membranes? 2) What structural properties of an ion channel permit ions to cross the membrane and account for the selectivity of the channel for a particular species of ion? By mutating particular residues of the cloned gene and expressing the mutant channels in oocytes we will ask how these changes influence function. A region whose sequence suggests that it may line the pore of the channel will be targeted. Can alterations within this region alter permeation or the selectivity of the channel for potassium? Together, these studies aim to elucidate the cell biology of an important class of channels and the mechanism by which these channels work.

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National Institute of General Medical Sciences (NIGMS)
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Physiology Study Section (PHY)
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Stanford University
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Guo, Weinong; Jung, W Edward; Marionneau, Celine et al. (2005) Targeted deletion of Kv4.2 eliminates I(to,f) and results in electrical and molecular remodeling, with no evidence of ventricular hypertrophy or myocardial dysfunction. Circ Res 97:1342-50
Zaritsky, J J; Redell, J B; Tempel, B L et al. (2001) The consequences of disrupting cardiac inwardly rectifying K(+) current (I(K1)) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes. J Physiol 533:697-710
Zaritsky, J J; Eckman, D M; Wellman, G C et al. (2000) Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation. Circ Res 87:160-6
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Villarroel, A; Schwarz, T L (1996) Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid. J Neurosci 16:1016-25
Villarroel, A; Schwarz, T L (1996) Inhibition of the Kv4 (Shal) family of transient K+ currents by arachidonic acid. J Neurosci 16:2522-32
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