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Activation gating in HCN2 channels

Author

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  • Sabine Hummert
  • Susanne Thon
  • Thomas Eick
  • Ralf Schmauder
  • Eckhard Schulz
  • Klaus Benndorf

Abstract

Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels control electrical rhythmicity in specialized brain and heart cells. We quantitatively analysed voltage-dependent activation of homotetrameric HCN2 channels and its modulation by the second messenger cAMP using global fits of hidden Markovian models to complex experimental data. We show that voltage-dependent activation is essentially governed by two separable voltage-dependent steps followed by voltage-independent opening of the pore. According to this model analysis, the binding of cAMP to the channels exerts multiple effects on the voltage-dependent gating: It stabilizes the open pore, reduces the total gating charge from ~8 to ~5, makes an additional closed state outside the activation pathway accessible and strongly accelerates the ON-gating but not the OFF-gating. Furthermore, the open channel has a much slower computed OFF-gating current than the closed channel, in both the absence and presence of cAMP. Together, these results provide detailed new insight into the voltage- and cAMP-induced activation gating of HCN channels.Author summary: Hyperpolarization-activated cyclic nucleotide-modulated (HCN) channels are tetrameric voltage-controlled ion channels in the cell membrane of specialized nerve and heart cells. Their main function is to generate a so-called pacemaker current which plays a key role in the generation of electrical rhythmicity. A special messenger molecule, cAMP, synthesized within these cells at sympathetic stimulation, can bind to these channels, thereby enhancing channel opening evoked by voltage. The mechanism of this dual activation is still poorly understood. Here we quantified this duality of activation for HCN2 channels by globally fitting hidden Markovian state models to extensive sets of data. We propose that activation of this tetrameric channel requires for a full description only two voltage-dependent steps that are followed by a voltage-independent opening step of the channel pore. According to this model analysis cAMP exerts multiple effects on channel activation: It notably accelerates the charge movement of the voltage-dependent steps and reduces the number of the involved electrical charges. Furthermore, it introduces an additional closed state and stabilizes the open pore. Together, our results provide new insight into the duality of voltage- and cAMP-induced activation of HCN channels.

Suggested Citation

  • Sabine Hummert & Susanne Thon & Thomas Eick & Ralf Schmauder & Eckhard Schulz & Klaus Benndorf, 2018. "Activation gating in HCN2 channels," PLOS Computational Biology, Public Library of Science, vol. 14(3), pages 1-18, March.
  • Handle: RePEc:plo:pcbi00:1006045
    DOI: 10.1371/journal.pcbi.1006045
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    References listed on IDEAS

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    1. Christoph Biskup & Jana Kusch & Eckhard Schulz & Vasilica Nache & Frank Schwede & Frank Lehmann & Volker Hagen & Klaus Benndorf, 2007. "Relating ligand binding to activation gating in CNGA2 channels," Nature, Nature, vol. 446(7134), pages 440-443, March.
    2. Andreas Ludwig & Xiangang Zong & Michael Jeglitsch & Franz Hofmann & Martin Biel, 1998. "A family of hyperpolarization-activated mammalian cation channels," Nature, Nature, vol. 393(6685), pages 587-591, June.
    3. Renate Gauss & Reinhard Seifert & U. Benjamin Kaupp, 1998. "Molecular identification of a hyperpolarization-activated channel in sea urchin sperm," Nature, Nature, vol. 393(6685), pages 583-587, June.
    4. Klaus Benndorf & Jana Kusch & Eckhard Schulz, 2012. "Probability Fluxes and Transition Paths in a Markovian Model Describing Complex Subunit Cooperativity in HCN2 Channels," PLOS Computational Biology, Public Library of Science, vol. 8(10), pages 1-10, October.
    5. William N. Zagotta & Nelson B. Olivier & Kevin D. Black & Edgar C. Young & Rich Olson & Eric Gouaux, 2003. "Structural basis for modulation and agonist specificity of HCN pacemaker channels," Nature, Nature, vol. 425(6954), pages 200-205, September.
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