Development of covalent chemogenetic K_2P channel activators.

ABSTRACT: K_2P potassium channels regulate excitability by affecting cellular resting membrane potential in the brain, cardiovascular system, immune cells, and sensory organs. Despite their important roles in anesthesia, arrhythmia, pain, hypertension, sleep, and migraine, the ability to control K_2P function remains limited. Here, we describe a chemogenetic strategy termed CATKLAMP (covalent activation of TREK family K⁺ channels to clamp membrane potential) that leverages the discovery of a K_2P modulator pocket site that reacts with electrophile-bearing derivatives of a TREK subfamily small-molecule activator, ML335, to activate the channel irreversibly. We show that CATKLAMP can be used to probe fundamental aspects of K_2P function, as a switch t

SUBMITTER: Deal PE 

PROVIDER: S-EPMC11433823 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature