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Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures.
Hammelmann, Verena; Stieglitz, Marc Sebastian; Hülle, Henrik; Le Meur, Karim; Kass, Jennifer; Brümmer, Manuela; Gruner, Christian; Rötzer, René Dominik; Fenske, Stefanie; Hartmann, Jana; Zott, Benedikt; Lüthi, Anita; Spahn, Saskia; Moser, Markus; Isbrandt, Dirk; Ludwig, Andreas; Konnerth, Arthur; Wahl-Schott, Christian; Biel, Martin.
Afiliación
  • Hammelmann V; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Stieglitz MS; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Hülle H; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Le Meur K; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Kass J; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Brümmer M; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Gruner C; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Rötzer RD; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Fenske S; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Hartmann J; Institute of Neuroscience, Technical University of Munich, Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy) and Center for Integrated Protein Sciences (CIPSM), Munich, Germany.
  • Zott B; Institute of Neuroscience, Technical University of Munich, Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy) and Center for Integrated Protein Sciences (CIPSM), Munich, Germany.
  • Lüthi A; Department of Fundamental Neurosciences, University of Lausanne, Lausanne, Switzerland.
  • Spahn S; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Moser M; Department for Molecular Medicine, Max-Planck-Institut für Biochemie, Martinsried, Germany.
  • Isbrandt D; DZNE Research Group, Experimental Neurophysiology, Institute for Molecular and Behavioral Neuroscience, University of Cologne, Germany.
  • Ludwig A; Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
  • Konnerth A; Institute of Neuroscience, Technical University of Munich, Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy) and Center for Integrated Protein Sciences (CIPSM), Munich, Germany.
  • Wahl-Schott C; Department of Pharmacy, Center for Drug Research, Center for Integrated Protein Science Munich, Ludwig-Maximilians-Universität München, Munich, Germany.
  • Biel M; Institut für Neurophysiologie, Medizinische Hochschule Hannover, Hannover, Germany.
JCI Insight ; 4(9)2019 05 02.
Article en En | MEDLINE | ID: mdl-31045576
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are dually gated channels that are operated by voltage and by neurotransmitters via the cAMP system. cAMP-dependent HCN regulation has been proposed to play a key role in regulating circuit behavior in the thalamus. By analyzing a knockin mouse model (HCN2EA), in which binding of cAMP to HCN2 was abolished by 2 amino acid exchanges (R591E, T592A), we found that cAMP gating of HCN2 is essential for regulating the transition between the burst and tonic modes of firing in thalamic dorsal-lateral geniculate (dLGN) and ventrobasal (VB) nuclei. HCN2EA mice display impaired visual learning, generalized seizures of thalamic origin, and altered NREM sleep properties. VB-specific deletion of HCN2, but not of HCN4, also induced these generalized seizures of the absence type, corroborating a key role of HCN2 in this particular nucleus for controlling consciousness. Together, our data define distinct pathological phenotypes resulting from the loss of cAMP-mediated gating of a neuronal HCN channel.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Convulsiones / AMP Cíclico / Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización Tipo de estudio: Diagnostic_studies Límite: Animals / Humans / Male Idioma: En Revista: JCI Insight Año: 2019 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Convulsiones / AMP Cíclico / Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización Tipo de estudio: Diagnostic_studies Límite: Animals / Humans / Male Idioma: En Revista: JCI Insight Año: 2019 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Estados Unidos