title: Mixing and matching TREK/TRAAK subunits generate heterodimeric K2P channels with unique properties.
abstract: The tandem of pore domain in a weak inwardly rectifying K(+) channel (Twik)-related acid-arachidonic activated K(+) channel (TRAAK) and Twik-related K(+) channels (TREK) 1 and TREK2 are active as homodimers gated by stretch, fatty acids, pH, and G protein-coupled receptors. These two-pore domain potassium (K2P) channels are broadly expressed in the nervous system where they control excitability. TREK/TRAAK KO mice display altered phenotypes related to nociception, neuroprotection afforded by polyunsaturated fatty acids, learning and memory, mood control, and sensitivity to general anesthetics. These channels have emerged as promising targets for the development of new classes of anesthetics, analgesics, antidepressants, neuroprotective agents, and drugs against addiction. Here, we show that the TREK1, TREK2, and TRAAK subunits assemble and form active heterodimeric channels with electrophysiological, regulatory, and pharmacological properties different from those of homodimeric channels. Heteromerization occurs between all TREK variants produced by alternative splicing and alternative translation initiation. These results unveil a previously unexpected diversity of K2P channels that will be challenging to analyze in vivo, but which opens new perspectives for the development of clinically relevant drugs.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique, CNRS, Université de Nice Sophia Antipolis, 06560 Valbonne, France;
authors.forename: Sandy
authors.initials: S
authors.lastname: Blin
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique, CNRS, Université de Nice Sophia Antipolis, 06560 Valbonne, France;
authors.forename: Ismail
authors.initials: I
authors.lastname: Ben Soussia
authors.affiliation: Department of Physiology, College of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, South Korea.
authors.forename: Eun-Jin
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique, CNRS, Université de Nice Sophia Antipolis, 06560 Valbonne, France;
authors.forename: Frédéric
authors.initials: F
authors.lastname: Brau
authors.affiliation: Department of Physiology, College of Medicine and Institute of Health Sciences, Gyeongsang National University, Jinju 660-751, South Korea lesage@ipmc.cnrs.fr dawon@gnu.ac.kr.
authors.forename: Dawon
authors.initials: D
authors.lastname: Kang
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique, CNRS, Université de Nice Sophia Antipolis, 06560 Valbonne, France; lesage@ipmc.cnrs.fr dawon@gnu.ac.kr.
authors.forename: Florian
authors.initials: F
authors.lastname: Lesage
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, Laboratoire d'Excellence Canaux Ioniques d'Intérêt Thérapeutique, CNRS, Université de Nice Sophia Antipolis, 06560 Valbonne, France;
authors.forename: Delphine
authors.initials: D
authors.lastname: Bichet
mesh_terms: D000818:Animals; D019281:Dimerization; D004285:Dogs; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D024683:Potassium Channels, Tandem Pore Domain / Q000737:chemistry*
chemical_list: D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1
keywords: electrophysiology; heteromerization; pharmacology; potassium channel; subunit assembly