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1 Molecular Neurophysiology and Biophysics Unit, Laboratory of Cellular and Synaptic Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA
A-type potassium channels regulate neuronal firing frequency and the back-propagation of action potentials (APs) into dendrites of hippocampal CA1 pyramidal neurones. Recent molecular cloning studies have found several families of voltage-gated K+ channel genes expressed in the mammalian brain. At present, information regarding the relationship between the protein products of these genes and the various neuronal functions performed by voltage-gated K+ channels is lacking. Here we used a combination of molecular, electrophysiological and imaging techniques to show that one such gene, Kv4.2, controls AP half-width, frequency-dependent AP broadening and dendritic action potential propagation. Using a modified Sindbis virus, we expressed either the enhanced green fluorescence protein (EGFP)-tagged Kv4.2 or an EGFP-tagged dominant negative mutant of Kv4.2 (Kv4.2gW362F) in CA1 pyramidal neurones of organotypic slice cultures. Neurones expressing Kv4.2gW362F displayed broader action potentials with an increase in frequency-dependent AP broadening during a train compared with control neurones. In addition, Ca2+ imaging of Kv4.2gW362F expressing dendrites revealed enhanced AP back-propagation compared to control neurones. Conversely, neurones expressing an increased A-type current through overexpression of Kv4.2 displayed narrower APs with less frequency dependent broadening and decreased dendritic propagation. These results point to Kv4.2 as the major contributor to the A-current in hippocampal CA1 neurones and suggest a prominent role for Kv4.2 in regulating AP shape and dendritic signalling. As Ca2+ influx occurs primarily during AP repolarization, Kv4.2 activity can regulate cellular processes involving Ca2+-dependent second messenger cascades such as gene expression and synaptic plasticity.
(Received 20 July 2005;
accepted after revision 30 August 2005;
first published online 1 September 2005)
Corresponding author D. Hoffman: Molecular Neurophysiology and Biophysics Unit, Laboratory of Synaptic and Cellular Neurophysiology, National Institute of Child Health and Human Development, National Institutes of Health, Porter Neuroscience Research Center, 35 Lincoln Drive, Building 35, Room 3C-905, Bethesda, MD 20892-3715, USA. Email: hoffmand{at}mail.nih.gov
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