Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are voltage-gated tetrameric cation channels that generate electrical rhythmicity in neurons and cardiomyocytes. Activation can be enhanced by the binding of adenosine-3',5'-cyclic monophosphate (cAMP) to an intracellul...

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Autores principales:	Klaus Benndorf, Jana Kusch, Eckhard Schulz
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/3dfd72b770b441fda9c7f0fc5594aa13
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spelling	oai:doaj.org-article:3dfd72b770b441fda9c7f0fc5594aa132021-11-18T05:52:47ZProbability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.1553-734X1553-735810.1371/journal.pcbi.1002721https://doaj.org/article/3dfd72b770b441fda9c7f0fc5594aa132012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23093920/pdf/?tool=EBIhttps://doaj.org/toc/1553-734Xhttps://doaj.org/toc/1553-7358Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are voltage-gated tetrameric cation channels that generate electrical rhythmicity in neurons and cardiomyocytes. Activation can be enhanced by the binding of adenosine-3',5'-cyclic monophosphate (cAMP) to an intracellular cyclic nucleotide binding domain. Based on previously determined rate constants for a complex Markovian model describing the gating of homotetrameric HCN2 channels, we analyzed probability fluxes within this model, including unidirectional probability fluxes and the probability flux along transition paths. The time-dependent probability fluxes quantify the contributions of all 13 transitions of the model to channel activation. The binding of the first, third and fourth ligand evoked robust channel opening whereas the binding of the second ligand obstructed channel opening similar to the empty channel. Analysis of the net probability fluxes in terms of the transition path theory revealed pronounced hysteresis for channel activation and deactivation. These results provide quantitative insight into the complex interaction of the four structurally equal subunits, leading to non-equality in their function.Klaus BenndorfJana KuschEckhard SchulzPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Computational Biology, Vol 8, Iss 10, p e1002721 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Klaus Benndorf Jana Kusch Eckhard Schulz Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.
description	Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are voltage-gated tetrameric cation channels that generate electrical rhythmicity in neurons and cardiomyocytes. Activation can be enhanced by the binding of adenosine-3',5'-cyclic monophosphate (cAMP) to an intracellular cyclic nucleotide binding domain. Based on previously determined rate constants for a complex Markovian model describing the gating of homotetrameric HCN2 channels, we analyzed probability fluxes within this model, including unidirectional probability fluxes and the probability flux along transition paths. The time-dependent probability fluxes quantify the contributions of all 13 transitions of the model to channel activation. The binding of the first, third and fourth ligand evoked robust channel opening whereas the binding of the second ligand obstructed channel opening similar to the empty channel. Analysis of the net probability fluxes in terms of the transition path theory revealed pronounced hysteresis for channel activation and deactivation. These results provide quantitative insight into the complex interaction of the four structurally equal subunits, leading to non-equality in their function.
format	article
author	Klaus Benndorf Jana Kusch Eckhard Schulz
author_facet	Klaus Benndorf Jana Kusch Eckhard Schulz
author_sort	Klaus Benndorf
title	Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.
title_short	Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.
title_full	Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.
title_fullStr	Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.
title_full_unstemmed	Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.
title_sort	probability fluxes and transition paths in a markovian model describing complex subunit cooperativity in hcn2 channels.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/3dfd72b770b441fda9c7f0fc5594aa13
work_keys_str_mv	AT klausbenndorf probabilityfluxesandtransitionpathsinamarkovianmodeldescribingcomplexsubunitcooperativityinhcn2channels AT janakusch probabilityfluxesandtransitionpathsinamarkovianmodeldescribingcomplexsubunitcooperativityinhcn2channels AT eckhardschulz probabilityfluxesandtransitionpathsinamarkovianmodeldescribingcomplexsubunitcooperativityinhcn2channels
_version_	1718424719970009088

Probability fluxes and transition paths in a Markovian model describing complex subunit cooperativity in HCN2 channels.

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