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Cytoplasmic Autoinhibition in HCN Channels is Regulated by the Transmembrane Region.
Page, Dana A; Magee, Kaylee E A; Li, Jessica; Jung, Matthew; Young, Edgar C.
Afiliación
  • Page DA; Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada.
  • Magee KEA; Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada.
  • Li J; Department of Biology, Kwantlen Polytechnic University, 12666 72 Avenue, Surrey, BC, V3W 2M8, Canada.
  • Jung M; Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada.
  • Young EC; Department of Molecular Biology and Biochemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, V5A 1S6, Canada.
J Membr Biol ; 253(2): 153-166, 2020 04.
Article en En | MEDLINE | ID: mdl-32146488
Hyperpolarization-activated cation-nonselective (HCN) channels regulate electrical activity in the brain and heart in a cAMP-dependent manner. The voltage-gating of these channels is mediated by a transmembrane (TM) region but is additionally regulated by direct binding of cAMP to a cyclic nucleotide-binding (CNB) fold in the cytoplasmic C-terminal region. Cyclic AMP potentiation has been explained by an autoinhibition model which views the unliganded CNB fold as an inhibitory module whose influence is disrupted by cAMP binding. However, the HCN2 subtype uses two other CNB fold-mediated mechanisms called open-state trapping and Quick-Activation to respectively slow the deactivation kinetics and speed the activation kinetics, against predictions of an autoinhibition model. To test how these multiple mechanisms are influenced by the TM region, we replaced the TM region of HCN2 with that of HCN4. This HCN4 TM-replacement preserved cAMP potentiation but augmented the magnitude of autoinhibition by the unliganded CNB fold; it moreover disrupted open-state trapping and Quick-Activation so that autoinhibition became the dominant mechanism contributed by the C-terminal region to determine kinetics. Truncation within the CNB fold partially relieved this augmented autoinhibition. This argues against the C-terminal region acting like a portable module with consistent effects on TM regions of different subtypes. Our findings provide evidence that functional interactions between the HCN2 TM region and C-terminal region govern multiple CNB fold-mediated mechanisms, implying that the molecular mechanisms of autoinhibition, open-state trapping, and Quick-Activation include participation of TM region structures.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dominios y Motivos de Interacción de Proteínas / Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización Tipo de estudio: Prognostic_studies Idioma: En Revista: J Membr Biol Año: 2020 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dominios y Motivos de Interacción de Proteínas / Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización Tipo de estudio: Prognostic_studies Idioma: En Revista: J Membr Biol Año: 2020 Tipo del documento: Article País de afiliación: Canadá Pais de publicación: Estados Unidos