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Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides
Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels play an important role in regulating electrical activity in the heart and brain. They are gated by the binding of cyclic nucleotides to a conserved, intracellular cyclic nucleotide-binding domain (CNBD), which is connected to the...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Biochemistry and Molecular Biology
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697172/ https://www.ncbi.nlm.nih.gov/pubmed/26559974 http://dx.doi.org/10.1074/jbc.M115.696450 |
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author | DeBerg, Hannah A. Brzovic, Peter S. Flynn, Galen E. Zagotta, William N. Stoll, Stefan |
author_facet | DeBerg, Hannah A. Brzovic, Peter S. Flynn, Galen E. Zagotta, William N. Stoll, Stefan |
author_sort | DeBerg, Hannah A. |
collection | PubMed |
description | Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels play an important role in regulating electrical activity in the heart and brain. They are gated by the binding of cyclic nucleotides to a conserved, intracellular cyclic nucleotide-binding domain (CNBD), which is connected to the channel pore by a C-linker region. Binding of cyclic nucleotides increases the rate and extent of channel activation and shifts it to less hyperpolarized voltages. We probed the allosteric mechanism of different cyclic nucleotides on the CNBD and on channel gating. Electrophysiology experiments showed that cAMP, cGMP, and cCMP were effective agonists of the channel and produced similar increases in the extent of channel activation. In contrast, electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) on the isolated CNBD indicated that the induced conformational changes and the degrees of stabilization of the active conformation differed for the three cyclic nucleotides. We explain these results with a model where different allosteric mechanisms in the CNBD all converge to have the same effect on the C-linker and render all three cyclic nucleotides similarly potent activators of the channel. |
format | Online Article Text |
id | pubmed-4697172 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | American Society for Biochemistry and Molecular Biology |
record_format | MEDLINE/PubMed |
spelling | pubmed-46971722016-01-11 Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides DeBerg, Hannah A. Brzovic, Peter S. Flynn, Galen E. Zagotta, William N. Stoll, Stefan J Biol Chem Molecular Biophysics Hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels play an important role in regulating electrical activity in the heart and brain. They are gated by the binding of cyclic nucleotides to a conserved, intracellular cyclic nucleotide-binding domain (CNBD), which is connected to the channel pore by a C-linker region. Binding of cyclic nucleotides increases the rate and extent of channel activation and shifts it to less hyperpolarized voltages. We probed the allosteric mechanism of different cyclic nucleotides on the CNBD and on channel gating. Electrophysiology experiments showed that cAMP, cGMP, and cCMP were effective agonists of the channel and produced similar increases in the extent of channel activation. In contrast, electron paramagnetic resonance (EPR) and nuclear magnetic resonance (NMR) on the isolated CNBD indicated that the induced conformational changes and the degrees of stabilization of the active conformation differed for the three cyclic nucleotides. We explain these results with a model where different allosteric mechanisms in the CNBD all converge to have the same effect on the C-linker and render all three cyclic nucleotides similarly potent activators of the channel. American Society for Biochemistry and Molecular Biology 2016-01-01 2015-11-11 /pmc/articles/PMC4697172/ /pubmed/26559974 http://dx.doi.org/10.1074/jbc.M115.696450 Text en © 2016 by The American Society for Biochemistry and Molecular Biology, Inc. Author's Choice—Final version free via Creative Commons CC-BY license (http://creativecommons.org/licenses/by/4.0) . |
spellingShingle | Molecular Biophysics DeBerg, Hannah A. Brzovic, Peter S. Flynn, Galen E. Zagotta, William N. Stoll, Stefan Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides |
title | Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides |
title_full | Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides |
title_fullStr | Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides |
title_full_unstemmed | Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides |
title_short | Structure and Energetics of Allosteric Regulation of HCN2 Ion Channels by Cyclic Nucleotides |
title_sort | structure and energetics of allosteric regulation of hcn2 ion channels by cyclic nucleotides |
topic | Molecular Biophysics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4697172/ https://www.ncbi.nlm.nih.gov/pubmed/26559974 http://dx.doi.org/10.1074/jbc.M115.696450 |
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