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Structural basis for hyperpolarization-dependent opening of human HCN1 channel.

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Hyperpolarization and cyclic nucleotide (HCN) activated ion channels, crucial for heart rhythm, activate upon hyperpolarization. New cryo-EM structures reveal how helix unwinding and pore dilation underlie this unusual voltage dependence.

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Area of Science:

  • Structural Biology
  • Biophysics
  • Molecular Physiology

Background:

  • Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are essential for cardiac pacemaking and neuronal electrical activity.
  • Unlike typical voltage-gated channels, HCN channels open upon membrane hyperpolarization, a mechanism termed inverted electromechanical coupling.
  • The precise structural basis for this unusual voltage dependence has remained elusive.

Purpose of the Study:

  • To elucidate the structural mechanisms underlying the hyperpolarization-activated gating of human HCN1 channels.
  • To visualize distinct functional states of HCN1 using high-resolution cryo-electron microscopy.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) was employed to determine the structures of human HCN1.
  • Structures were obtained corresponding to Closed, Open, and a putative Intermediate gating states.

Main Results:

  • The structures reveal a novel gating mechanism involving the unwinding of the inner S4 and S5 helices upon hyperpolarization.
  • This helix-coil transition disrupts the intracellular gating interface and is coupled to an iris-like dilation of the pore helices.
  • These conformational changes directly explain the reversed voltage dependence of HCN channels.

Conclusions:

  • The study provides the first high-resolution structural insights into the unique gating of HCN channels.
  • The findings reveal a conserved mechanism of inverted electromechanical coupling involving helix unwinding and pore dilation.
  • This work advances our understanding of cardiac automaticity and neuronal excitability regulated by HCN channels.