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cAMP binding to closed pacemaker ion channels is non-cooperative

Author

Listed:
  • David S. White

    (University of Wisconsin-Madison
    University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Sandipan Chowdhury

    (University of Wisconsin-Madison
    University of Iowa Carver College of Medicine)

  • Vinay Idikuda

    (University of Wisconsin-Madison
    Washington University School of Medicine)

  • Ruohan Zhang

    (University of Wisconsin-Madison
    University of Wisconsin-Madison)

  • Scott T. Retterer

    (Oak Ridge National Laboratory)

  • Randall H. Goldsmith

    (University of Wisconsin-Madison)

  • Baron Chanda

    (University of Wisconsin-Madison
    Washington University School of Medicine)

Abstract

Electrical activity in the brain and heart depends on rhythmic generation of action potentials by pacemaker ion channels (HCN) whose activity is regulated by cAMP binding1. Previous work has uncovered evidence for both positive and negative cooperativity in cAMP binding2,3, but such bulk measurements suffer from limited parameter resolution. Efforts to eliminate this ambiguity using single-molecule techniques have been hampered by the inability to directly monitor binding of individual ligand molecules to membrane receptors at physiological concentrations. Here we overcome these challenges using nanophotonic zero-mode waveguides4 to directly resolve binding dynamics of individual ligands to multimeric HCN1 and HCN2 ion channels. We show that cAMP binds independently to all four subunits when the pore is closed, despite a subsequent conformational isomerization to a flip state at each site. The different dynamics in binding and isomerization are likely to underlie physiologically distinct responses of each isoform to cAMP5 and provide direct validation of the ligand-induced flip-state model6–9. This approach for observing stepwise binding in multimeric proteins at physiologically relevant concentrations can directly probe binding allostery at single-molecule resolution in other intact membrane proteins and receptors.

Suggested Citation

  • David S. White & Sandipan Chowdhury & Vinay Idikuda & Ruohan Zhang & Scott T. Retterer & Randall H. Goldsmith & Baron Chanda, 2021. "cAMP binding to closed pacemaker ion channels is non-cooperative," Nature, Nature, vol. 595(7868), pages 606-610, July.
  • Handle: RePEc:nat:nature:v:595:y:2021:i:7868:d:10.1038_s41586-021-03686-x
    DOI: 10.1038/s41586-021-03686-x
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    Cited by:

    1. Verena Burtscher & Jonathan Mount & Jian Huang & John Cowgill & Yongchang Chang & Kathleen Bickel & Jianhan Chen & Peng Yuan & Baron Chanda, 2024. "Structural basis for hyperpolarization-dependent opening of human HCN1 channel," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    2. Vishal R. Patel & Arturo M. Salinas & Darong Qi & Shipra Gupta & David J. Sidote & Marcel P. Goldschen-Ohm, 2021. "Single-molecule imaging with cell-derived nanovesicles reveals early binding dynamics at a cyclic nucleotide-gated ion channel," Nature Communications, Nature, vol. 12(1), pages 1-13, December.

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