Development of covalent chemogenetic K2Pchannel activators

Abstract

AbstractK2Ppotassium 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 K2Pfunction remains limited. Here, we describe a chemogenetic strategy termed CATKLAMP (CovalentActivation ofTREK familyK+channels to cLAmpMembranePotential) that leverages the discovery of a site in the K2Pmodulator pocket that reacts with electrophile-bearing derivatives of a TREK subfamily small molecule activator, ML335, to activate the channel irreversibly. We show that the CATKLAMP strategy can be used to probe fundamental aspects of K2Pfunction, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members. Together, our findings exemplify a new means to alter K2Pchannel activity that should facilitate studies both molecular and systems level studies of K2Pfunction and enable the search for new K2Pmodulators.