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Recapitulation of an Ion Channel IV Curve Using Frequency Components

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Published on: February 8, 2011

A second S4 movement opens hyperpolarization-activated HCN channels.

Xiaoan Wu¹, Rosamary Ramentol¹, Marta E Perez¹

¹Department of Physiology and Biophysics, University of Miami, Miami, FL 33136.

Proceedings of the National Academy of Sciences of the United States of America

|September 10, 2021

Summary

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels open via a two-step S4 movement. A specific mutation reveals a second S4 movement linked to channel gating, uncovering the mechanism of HCN channel opening.

Keywords:

S4 movement S4-to-gate coupling molecular models spHCN voltage clamp fluorometry

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Area of Science:

Biophysics
Molecular Biology
Cardiology

Background:

Pacemaker cell rhythmic activity relies on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
The S4 transmembrane segment acts as a voltage sensor in HCN channels, similar to K+ channels.

Purpose of the Study:

To elucidate the mechanism by which S4 movement in HCN channels couples to channel opening at hyperpolarized voltages.
To investigate the distinct voltage-dependent steps of S4 movement and their relation to channel gating.

Main Methods:

Voltage clamp fluorometry was employed to monitor S4 movement in HCN channels.
Site-directed mutagenesis was used to create and study the E356A mutation in sea urchin HCN channels.
Cysteine accessibility studies and molecular modeling provided structural insights.

Main Results:

S4 in HCN channels exhibits a two-step movement in response to hyperpolarization, with the second step correlating with channel opening.
The E356A mutation in S4 uncoupled the voltage dependence of the main S4 movement from channel opening.
This mutation revealed a distinct S4 movement at negative voltages associated with gate opening and suggested an intracellular crevice formation.

Conclusions:

The study identified a two-step S4 movement mechanism underlying HCN channel gating.
The E356A mutation provides a tool to dissect the coupling between voltage sensing and pore opening.
Structural models suggest that S4 movement creates an intracellular crevice, facilitating pore opening by S5 and S6 segments.