Development of covalent chemogenetic K2P channel activators

Parker E Deal; Haerim Lee; Abhisek Mondal; Marco Lolicato; Philipe Ribeiro Furtado de Mendonça; Holly Black; Seil Jang; Xochina El-Hilali; Clifford Bryant; Ehud Y Isacoff; Adam R Renslo; Daniel L Minor Jr

doi:10.1016/j.chembiol.2024.06.006

Development of covalent chemogenetic K_2P channel activators

Cell Chem Biol. 2024 Jul 18;31(7):1305-1323.e9. doi: 10.1016/j.chembiol.2024.06.006.

Affiliations

¹ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 93858-2330, USA; Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 93858-2330, USA.
² Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 93858-2330, USA.
³ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁴ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 93858-2330, USA.
⁵ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Weill Neurohub, University of California, Berkeley, Berkeley, CA 94720, USA; Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA.
⁶ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 93858-2330, USA. Electronic address: adam.renslo@ucsf.edu.
⁷ Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 93858-2330, USA; Molecular Biophysics and Integrated Bio-imaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720 USA; Departments of Biochemistry and Biophysics, and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 93858-2330, USA; California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 93858-2330, USA; Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, San Francisco, CA 93858-2330, USA. Electronic address: daniel.minor@ucsf.edu.

PMID: 39029456
DOI: 10.1016/j.chembiol.2024.06.006

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 to silence neuronal firing, and is applicable to all TREK subfamily members. Together, our findings exemplify a means to alter K_2P channel activity that should facilitate molecular and systems level studies of K_2P function and enable the search for new K_2P modulators.

Keywords: K(2P) channel; ML335; TREK-1; X-ray crystallography; chemogenetics; electrophysiology; potassium channel.

MeSH terms

Animals
HEK293 Cells
Humans
Membrane Potentials / drug effects
Mice
Neurons / drug effects
Neurons / metabolism
Potassium Channels, Tandem Pore Domain* / genetics
Potassium Channels, Tandem Pore Domain* / metabolism
Rats

Substances

Potassium Channels, Tandem Pore Domain