An Allosteric Model for Electromechanical Coupling in Cardiac CNBD Channels

Area of Science:

• Molecular and Cellular Biology
• Biophysics
• Cardiovascular Physiology

Background:

• Ion channels in the cyclic nucleotide-binding domain (CNBD) family, including HCN and hERG channels, are crucial for cardiac action potentials.
• HCN channels activate via hyperpolarization for pacemaker activity, while hERG channels activate via depolarization for repolarization.
• Some hERG mutations cause abnormal biphasic activation, and a unified gating mechanism for CNBD channels is lacking.

Purpose of the Study:

• To propose a unified allosteric model for electromechanical coupling in CNBD ion channels.
• To explain the diverse voltage-dependent gating behaviors observed in these channels.
• To elucidate the specific roles of different channel domains in gating.

Main Methods:

• Developed a novel allosteric model with few parameters to describe channel gating.
• Utilized fluorescence anisotropy-based homo-FRET experiments with site-specific noncanonical amino acids.
• Analyzed conductance-voltage relationships to validate the model's predictions.

Main Results:

• The proposed model successfully recapitulates biphasic U-shaped and bell-shaped conductance-voltage relationships.
• The model features a single voltage-sensor transition coupled to two distinct conformational coupling modes.
• Experimental data support the model, indicating S5 helix movement for hyperpolarization gating and S4-S6 interactions for depolarization gating.

Conclusions:

• A unified allosteric framework explains diverse CNBD channel gating.
• Distinct electromechanical coupling mechanisms underlie hyperpolarization and depolarization activation.
• The model provides insights into channel function and dysfunction, particularly in cardiac conditions.