An allosteric modulator activates BK channels by perturbing coupling between Ca²⁺ binding and pore opening

Area of Science:

• Biophysics
• Molecular Biology
• Ion Channel Function

Background:

• BK channels are calcium (Ca²⁺)-activated potassium channels crucial for cellular excitability.
• Channel activation involves voltage sensor domain (VSD) and Ca²⁺ binding to the cytosolic tail domain (CTD).
• The precise coupling mechanisms between VSD activation, Ca²⁺ binding, and pore opening remain unclear.

Purpose of the Study:

• To investigate the allosteric modulation of BK channel activation by a novel compound, BC5.
• To elucidate the role of the CTD-VSD interface in Ca²⁺-dependent BK channel gating.
• To identify potential sites for allosteric drug development targeting BK channels.

Main Methods:

• In silico screening to identify the compound BC5.
• Biochemical assays to study BC5 interaction with the CTD-VSD interface.
• Mutagenesis studies to probe functional mechanisms.
• Atomistic simulations to support experimental findings.

Main Results:

• BC5 specifically modulates the Ca²⁺-dependent activation pathway of BK channels.
• BC5 activates the channel independently of Ca²⁺ binding, but Ca²⁺ binding inhibits BC5's effects.
• The CTD-VSD interface is critical for coupling Ca²⁺ binding to pore opening and is a target for allosteric modulation.

Conclusions:

• The CTD-VSD interaction plays a significant role in the Ca²⁺-dependent activation mechanism of BK channels.
• BC5 acts as an allosteric modulator by perturbing the CTD-VSD coupling pathway.
• The CTD-VSD interface represents a key site for developing allosteric modulators of BK channel activity.