Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2.
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.
Ludwig
Andreas
A
Institut für Pharmakologie und Toxikologie, Technische Universität München, D-80802 München, Germany. ludwig@ipt.med.tu-muenchen.de
Budde
Thomas
T
Stieber
Juliane
J
Moosmang
Sven
S
Wahl
Christian
C
Holthoff
Knut
K
Langebartels
Anke
A
Wotjak
Carsten
C
Munsch
Thomas
T
Zong
Xiangang
X
Feil
Susanne
S
Feil
Robert
R
Lancel
Marike
M
Chien
Kenneth R
KR
Konnerth
Arthur
A
Pape
Hans-Christian
HC
Biel
Martin
M
Hofmann
Franz
F
D000818:Animals; D001146:Arrhythmia, Sinus / Q000235:genetics / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism; D004562:Electrocardiography; D004832:Epilepsy, Absence / Q000235:genetics / Q000378:metabolism*; D018390:Gene Targeting; D017930:Genes, Reporter; D006339:Heart Rate / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D007473:Ion Channels / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009124:Muscle Proteins / Q000235:genetics* / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D015221:Potassium Channels; D021122:Protein Subunits; D011995:Recombination, Genetic; D012849:Sinoatrial Node / Q000166:cytology / Q000378:metabolism; D013788:Thalamus / Q000378:metabolism
C578711:Hcn2 protein, mouse; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D009124:Muscle Proteins; D015221:Potassium Channels; D021122:Protein Subunits