KCNE3 acts by promoting voltage sensor activation in KCNQ1

Area of Science:

• Molecular biology
• Ion channel physiology
• Biophysics

Background:

• KCNE β-subunits modulate voltage-gated K(+) channels.
• KCNE3 and KCNQ1 form channels crucial for ion secretion in colon, stomach, and kidney.
• The mechanism by which KCNE3 confers apparent voltage independence to KCNQ1 channels is not fully understood.

Purpose of the Study:

• To investigate how KCNE3 affects the voltage sensor S4 and gate of KCNQ1 channels.
• To elucidate the molecular determinants of KCNE3's effect on KCNQ1 channel function.

Main Methods:

• Voltage clamp fluorometry was employed to study KCNQ1/KCNE3 channel dynamics.
• Mutagenesis and PIP2 depletion were used to separate S4 movement from gate opening.
• Electrophysiological recordings and analysis of charge interactions.

Main Results:

• KCNE3 causes S4 movement in KCNQ1 channels, which normally closes the gate.
• KCNE3 shifts the voltage dependence of S4 movement to hyperpolarized potentials, leading to constitutive conduction.
• KCNE3 directly impacts S4 movement, with specific acidic residues (D54, D55) interacting electrostatically with KCNQ1's R228.

Conclusions:

• KCNE3 primarily modulates the voltage-sensing domain of KCNQ1 channels.
• The observed constitutive conduction of KCNQ1/KCNE3 channels results from KCNE3's effect on S4 voltage dependence.
• Electrostatic interactions between KCNE3 and KCNQ1 are critical for channel modulation.