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| Subject Categories: Membranes & Transport | Molecular Biology of Disease |
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| The EMBO Journal
(2003) 22, 216–224, doi:10.1093/emboj/cdg032 |
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| Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2 |
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| Andreas Ludwig1, Thomas Budde2, Juliane Stieber1, Sven Moosmang1, Christian Wahl3, Knut Holthoff4, Anke Langebartels5, Carsten Wotjak6, Thomas Munsch2, Xiangang Zong3, Susanne Feil1, Robert Feil1, Marike Lancel5, Kenneth R. Chien7, Arthur Konnerth4, Hans-Christian Pape2, Martin Biel3 and Franz Hofmann1 |
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1 Institut für Pharmakologie und Toxikologie, Technische Universität München, D-80802 München, Germany 2 Institut für Physiologie, Otto-von-Guericke Universität, D-39120 Magdeburg, Germany 3 Department für Pharmazie, Ludwig-Maximilians Universität, D-81377 München, Germany 4 Institut für Physiologie, Ludwig-Maximilians Universität, D-80336 München, Germany 5 Schlafpharmakologie, Max-Planck-Institut für Psychiatrie, D-80804 München, Germany 6 Mausverhalten/Neuronale Plastizität, Max-Planck-Institut für Psychiatrie, D-80804 München, Germany 7 UCSD Institute of Molecular Medicine, La Jolla, CA 92093, USA To whom correspondence should be addressed Andreas Ludwig, ludwig@ipt.med.tu-muenchen.de Received 16 May 2002; Revised 24 October 2002; Accepted 19 November 2002. |
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| Abstract |
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| Hyperpolarization-activated cation (HCN) channels are believed to be involved in the generation of cardiac pacemaker depolarizations as well as in the control of neuronal excitability and plasticity. The contributions of the four individual HCN channel isoforms (HCN1–4) to these diverse functions are not known. Here we show that HCN2-deficient mice exhibit spontaneous absence seizures. The thalamocortical relay neurons of these mice displayed a near complete loss of the HCN current, resulting in a pronounced hyperpolarizing shift of the resting membrane potential, an altered response to depolarizing inputs and an increased susceptibility for oscillations. HCN2-null mice also displayed cardiac sinus dysrhythmia, a reduction of the sinoatrial HCN current and a shift of the maximum diastolic potential to hyperpolarized values. Mice with cardiomyocyte- specific deletion of HCN2 displayed the same dysrhythmia as mice lacking HCN2 globally, indicating that the dysrhythmia is indeed caused by sinoatrial dysfunction. Our results define the physiological role of the HCN2 subunit as a major determinant of membrane resting potential that is required for regular cardiac and neuronal rhythmicity. |
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| Keywords: epilepsy, HCN channel, heart, membrane potential, pacemaker current |
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