Initial steps of inactivation at the K+ channel selectivity filter

Area of Science:

• Biophysics
• Molecular Biology
• Ion Channel Physiology

Background:

• C-type inactivation of potassium channels controls ion flux via conformational changes near the selectivity filter.
• The precise molecular mechanisms initiating this inactivation, particularly the role of ion binding, remain incompletely understood.

Purpose of the Study:

• To elucidate the molecular forces driving the initiation of C-type inactivation in potassium channels.
• To investigate the differential roles of divalent cations, specifically Ca(2+) and Mg(2+), in modulating MthK channel inactivation.

Main Methods:

• Electrophysiology was employed to measure K(+) efflux and channel activity.
• Molecular simulations were utilized to visualize ion interactions within the MthK channel pore.

Main Results:

• Both Ca(2+) and Mg(2+) reduced K(+) efflux, but only Ca(2+) enhanced entry into the inactivated state.
• Molecular simulations revealed selective Ca(2+) accessibility to a site at the selectivity filter entrance, driven by partial dehydration.
• Ca(2+) binding at this site directly interacts with K(+) ions in the selectivity filter, inducing a conformational change and subsequent inactivation.

Conclusions:

• An ionic mechanism, involving Ca(2+) binding and interaction with K(+) ions, precedes conformational changes to initiate C-type inactivation.
• This study provides a detailed molecular understanding of how specific ions trigger inactivation in potassium channels.