2. Academic Validation
  3. Development of covalent chemogenetic K2P channel activators

Development of covalent chemogenetic K2P channel activators

  • Cell Chem Biol. 2024 Jul 18;31(7):1305-1323.e9. doi: 10.1016/j.chembiol.2024.06.006.
Parker E Deal 1,  Haerim Lee 2,  Abhisek Mondal 2,  Marco Lolicato 2,  Philipe Ribeiro Furtado de Mendonça 3,  Holly Black 3,  Seil Jang 2,  Xochina El-Hilali 4,  Clifford Bryant 4,  Ehud Y Isacoff 5,  Adam R Renslo 6,  Daniel L Minor Jr 7
Affiliations

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: [email protected].
  • 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: [email protected].
PMID: 39029456 DOI: 10.1016/j.chembiol.2024.06.006
Abstract

K2P 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 K2P 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 K2P 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 K2P function, as a switch to silence neuronal firing, and is applicable to all TREK subfamily members. Together, our findings exemplify a means to alter K2P channel activity that should facilitate molecular and systems level studies of K2P function and enable the search for new K2P modulators.

Keywords

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

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