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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

Functional properties of a brain-specific NH₂-terminally spliced modulator of Kv4 channels

¹Department of Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455; ²Department of Physiology, Virginia Commonwealth University, Richmond, Virginia 23298; and Departments of ³Physiology and ⁴Animal Science, University of Minnesota, St. Paul, Minnesota

Submitted 9 September 2002 ; accepted in final form 17 March 2003

Kv4/K channel-interacting protein (KChIP) potassium channels are a major class of rapidly inactivating K channels in brain and heart. Considering the importance of alternative splicing to the quantitative features of KChIP gating modulation, a previously uncharacterized splice form of KChIP1 was functionally characterized. The KChIP1b splice variant differs from the previously characterized KChIP1a splice form by the inclusion of a novel amino-terminal region that is encoded by an alternative exon that is conserved in mouse, rat, and human genes. The expression of KChIP1b mRNA was high in brain but undetectable in heart or liver by RT-PCR. In cerebellar tissue, KChIP1b and KChIP1a transcripts were expressed at nearly equal levels. Coexpression of KChIP1b or KChIP1a with Kv4.2 channels in oocytes slowed K current decay and destabilized open-inactivated channel gating. Like other KChIP subunits, KChIP1b increased Kv4.2 current amplitude and KChIP1b also shifted Kv4.2 conductance-voltage curves by —10 mV. The development of Kv4.2 channel inactivation accessed from closed gating states was faster with KChIP1b coexpression. Deletion of the novel amino-terminal region in KChIP1b selectively altered the subunit's modulation of Kv4.2 closed inactivation gating. The role of the KChIP1b NH₂-terminal region was further confirmed by direct comparison of the properties of the NH₂-terminal deletion mutant and the KChIP1a subunit, which is encoded by a transcript that lacks the novel exon. The features of KChIP1b modulation of Kv4 channels are likely to be conserved in mammals and demonstrate a role for the KChIP1 NH₂-terminal region in the regulation of closed inactivation gating.

inactivation; gating; mutagenesis; K channel-interacting protein; exon

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