Evaluating sequential and allosteric activation models in IKs channels with mutated voltage sensors

Area of Science:

• Molecular Biology
• Biophysics
• Cardiovascular Physiology

Background:

• The IKs channel complex is vital for cardiac repolarization and preventing arrhythmias.
• It consists of KCNQ1 α-subunits and KCNE1 accessory subunits.
• Understanding its activation mechanism is key to cardiac health.

Purpose of the Study:

• To determine the precise mechanism of IKs channel activation.
• To compare the efficacy of sequential versus allosteric models in explaining channel kinetics.
• To investigate the role of voltage sensor movement in channel gating.

Main Methods:

• Utilized an E160R mutation in KCNQ1 to control voltage sensor activation.
• Employed Markov models to simulate channel behavior.
• Integrated experimental data including steady-state and transient kinetics, voltage-sensor fluorescence, and limiting slope currents.

Main Results:

• Sequential models failed to explain activation delays and shifts in conductance-voltage relationships.
• Allosteric models with one transition per voltage sensor better simulated low open probability currents.
• Tiered allosteric models with two transitions per voltage sensor fully accounted for IKs current and fluorescence kinetics.

Conclusions:

• Allosteric models provide a more accurate representation of IKs channel activation than sequential models.
• Not all four voltage sensors need to move for IKs conductance.
• This research refines our understanding of ion channel gating relevant to cardiac function.