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Structural basis for modulation and agonist specificity of HCN pacemaker channels

Author

Listed:
  • William N. Zagotta

    (University of Washington School of Medicine)

  • Nelson B. Olivier

    (Columbia University)

  • Kevin D. Black

    (University of Washington School of Medicine)

  • Edgar C. Young

    (Columbia University)

  • Rich Olson

    (Columbia University)

  • Eric Gouaux

    (Columbia University
    Columbia University)

Abstract

The family of hyperpolarization-activated, cyclic nucleotide-modulated (HCN) channels are crucial for a range of electrical signalling, including cardiac and neuronal pacemaker activity, setting resting membrane electrical properties and dendritic integration1. These nonselective cation channels, underlying the If, Ih and Iq currents of heart and nerve cells, are activated by membrane hyperpolarization and modulated by the binding of cyclic nucleotides such as cAMP and cGMP2. The cAMP-mediated enhancement of channel activity is largely responsible for the increase in heart rate caused by β-adrenergic agonists3. Here we have investigated the mechanism underlying this modulation by studying a carboxy-terminal fragment of HCN2 containing the cyclic nucleotide-binding domain (CNBD) and the C-linker region that connects the CNBD to the pore. X-ray crystallographic structures of this C-terminal fragment bound to cAMP or cGMP, together with equilibrium sedimentation analysis, identify a tetramerization domain and the mechanism for cyclic nucleotide specificity, and suggest a model for ligand-dependent channel modulation. On the basis of amino acid sequence similarity to HCN channels, the cyclic nucleotide-gated, and eag- and KAT1-related families of channels are probably related to HCN channels in structure and mechanism.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:425:y:2003:i:6954:d:10.1038_nature01922
    DOI: 10.1038/nature01922
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    Cited by:

    1. Alessandro Porro & Andrea Saponaro & Roberta Castelli & Bianca Introini & Anahita Hafez Alkotob & Golnaz Ranjbari & Uta Enke & Jana Kusch & Klaus Benndorf & Bina Santoro & Dario DiFrancesco & Gerhard , 2024. "A high affinity switch for cAMP in the HCN pacemaker channels," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    2. Zhengshan Hu & Xiangdong Zheng & Jian Yang, 2023. "Conformational trajectory of allosteric gating of the human cone photoreceptor cyclic nucleotide-gated channel," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. 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.

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