Development of covalent chemogenetic K_2P channel activators

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Potassium (K2P) channels are crucial regulators of cellular excitability in various physiological systems.
• Dysfunction of K2P channels is implicated in numerous conditions, including pain, hypertension, and neurological disorders.
• Current methods for modulating K2P channel activity are limited, hindering research and therapeutic development.

Purpose of the Study:

• To develop a novel chemogenetic strategy for irreversible activation of K2P channels.
• To investigate the potential of this strategy in controlling neuronal activity and probing K2P channel function.
• To establish a versatile tool applicable to all TREK subfamily members.

Main Methods:

• Discovery of a specific K2P modulator pocket site.
• Design and synthesis of electrophile-bearing derivatives of the TREK activator ML335.
• Development of the CATKLAMP (covalent activation of TREK family K+ channels to clamp membrane potential) strategy.

Main Results:

• CATKLAMP enables irreversible activation of K2P channels by targeting a specific modulator pocket.
• The strategy was successfully applied to all TREK subfamily members.
• CATKLAMP demonstrated efficacy in silencing neuronal firing, serving as a molecular switch.

Conclusions:

• CATKLAMP provides a powerful new chemogenetic tool for precise control of K2P channel activity.
• This method facilitates fundamental research into K2P channel function at molecular and systems levels.
• CATKLAMP may accelerate the discovery of new K2P channel modulators for therapeutic applications.