Structural basis for hyperpolarization-dependent opening of human HCN1 channel

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.