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Probing the structural basis for differential KCNQ1 modulation by KCNE1 and KCNE2.

Yuhong Wang¹, Mei Zhang, Yu Xu

¹Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23298, USA.

The Journal of General Physiology

|November 28, 2012

Summary

KCNE1 and KCNE2 modulate KCNQ1 channels differently. Their transmembrane domains interact uniquely with KCNQ1, explaining differences in current amplitude and gating kinetics.

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Area of Science:

Cardiovascular Physiology
Molecular Cardiology
Ion Channel Biophysics

Background:

KCNE1 and KCNE2 are accessory subunits that modulate KCNQ1 potassium channel function.
KCNE1 enhances KCNQ1 current amplitude and slows activation, crucial for cardiac repolarization.
KCNE2 suppresses KCNQ1 current amplitude and slows deactivation, with unclear structural underpinnings for these distinct effects.

Purpose of the Study:

To elucidate the structural basis for the differential effects of KCNE1 and KCNE2 on KCNQ1 channel function.
To compare the interactions of KCNE1 and KCNE2 transmembrane domains (TMDs) and extracellular juxtamembrane (EJM) regions with KCNQ1.

Main Methods:

Cysteine scanning mutagenesis of KCNE1 and KCNE2 TMDs and EJMs.
Functional analysis of KCNQ1 channel activity following mutagenesis.
Probing subunit interactions using disulfide formation and methanethiosulfonate reagents.

Main Results:

The TMDs of KCNE1 and KCNE2 are similarly located but interact differently with KCNQ1.
Closer interaction of KCNE2 TMD with KCNQ1 suggests allosteric modulation of pore conductance, explaining amplitude differences.
KCNE1 EJM intimately contacts KCNQ1, while a crevice exists between KCNE2 and KCNQ1, potentially affecting gating kinetics.

Conclusions:

Differential interactions of KCNE1 and KCNE2 TMDs with KCNQ1 underlie their distinct effects on current amplitude.
Variations in EJM-KCNQ1 interactions, including the putative crevice for KCNE2, contribute to differing gating kinetics.
Structural insights into KCNE subunit modulation of KCNQ1 are crucial for understanding cardiac electrophysiology.