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CELLULAR |
1 Institute of Applied Physiology, University Hospital Hamburg-Eppendorf, University of Hamburg, Martinistr. 52, D-20246 Hamburg, Germany
2 Department of Neurology, University of Pennsylvania, 409 Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104-6060, USA
3 Department of Clinical Neuroscience, Graduate School of Medicine, University of Tokushima, 2-50-1 Kuramotocho, Tokushima City, 770-8503 Japan
4 Sobell Department of Neurophysiology, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK
Mutations that reduce the function of KCNQ2 channels cause neuronal hyperexcitability, manifested as epileptic seizures and myokymia. These channels are present in nodes of Ranvier in rat brain and nerve and have been proposed to mediate the slow nodal potassium current IKs. We have used immunocytochemistry, electrophysiology and pharmacology to test this hypothesis and to determine the contribution of KCNQ channels to nerve excitability in the rat. When myelinated nerve fibres of the sciatic nerve were examined by immunofluorescence microscopy using antibodies against KCNQ2 and KCNQ3, all nodes showed strong immunoreactivity for KCNQ2. The nodes of about half the small and intermediate sized fibres showed labelling for both KCNQ2 and KCNQ3, but nodes of large fibres were labelled by KCNQ2 antibodies only. In voltage-clamp experiments using large myelinated fibres, the selective KCNQ channel blockers XE991 (IC50 = 2.2 µM) and linopirdine (IC50 = 5.5 µM) completely inhibited IKs, as did TEA (IC50 = 0.22 mM). The KCNQ channel opener retigabine (10 µM) shifted the activation curve to more negative membrane potentials by –24 mV, thereby increasing IKs. In isotonic KCl 50% of IKs was activated at –62 mV. The activation curve shifted to more positive potentials as [K+]o was reduced, so that the pharmacological and biophysical properties of IKs were consistent with those of heterologously expressed homomeric KCNQ2 channels. The ability of XE991 to selectively block IKs was further exploited to study IKs function in vivo. In anaesthetized rats, the excitability of tail motor axons was indicated by the stimulus current required to elicit a 40% of maximal compound muscle action potential. XE991 (2.5 mg kg–1 I.P.) eliminated all nerve excitability functions previously attributed to IKs: accommodation to 100 ms subthreshold depolarizing currents, the post-depolarization undershoot in excitability, and the late subexcitability after a single impulse or short trains of impulses. Due to reduced spike-frequency adaptation after XE991 treatment, 100 ms suprathreshold current injections generated long trains of action potentials. We conclude that the nodal IKs current is mediated by KCNQ channels, which in large fibres of rat sciatic nerve appear to be KCNQ2 homomers.
(Received 2 February 2006;
accepted after revision 2 March 2006;
first published online 9 March 2006)
Corresponding author J. R. Schwarz: Institute of Applied Physiology, University Hospital Hamburg-Eppendorf, Martinistr. 52, D-20246 Hamburg, Germany. Email: schwarz{at}uke.uni-hamburg.de
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