Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P 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 Twikrelated 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 (K 2P ) 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 K 2P channels that will be challenging to analyze in vivo, but which opens new perspectives for the development of clinically relevant drugs. + channels (TREK) 1, TREK2, and Twik-related acid-arachidonic activated K + channel (TRAAK) channels produce inhibitory background K + currents (1-3). These channels respond to neuroprotective fatty acids, mechanical stretch, temperature, pH, and neurotransmitters through G proteincoupled receptors (GPCRs) (for a recent review, see ref. 4). TREK1 is activated by volatile anesthetics and plays a role in general anesthesia. These channels have emerged as promising targets for the development of other classes of clinical compounds. TREK1 is activated by opioid receptors and contributes to morphine-induced analgesia, but is not involved in morphine-induced constipation, respiratory depression, and dependence (5). TREK1 openers, acting downstream from opioid receptors, might have strong analgesic effects without adverse effects (6). TRAAK may also be a good target for analgesia: Its activation by angiotensin II receptors is responsible for the painless nature of the early lesions of the necrotizing tropical disease Buruli ulcer (7). Also, activation of TREK1 by GABA B receptors in the hippocampus (8), and inhibition of TREK2 by neurotensin receptors in the entorhinal cortex (9), suggests that specific modulators of these channels might also have beneficial actions against drug abuse, and against learning slow down and memory deficits in Alzheimer's disease. Finally, inhibition of TREK1 by spadin (10), an endogenous peptide, or by the antidepressant fluoxetine (Prozac) (11), pinpoints it as a valuable target for the treatment of depression. TREK/TRAAK channels are broadly expressed in the nervous system (12-15). TREK1 is more specifically expressed in the striatum, TREK2 in the cerebellum, and TRAAK in the thalamus. All...

Chemically Modified Derivatives of the Activator Compound Cloxyquin Exert Inhibitory Effect on TRESK (K2P18.1) Background Potassium Channel

“…We have previously described that RR inhibits background K 1 currents in DRG neurons (Braun et al, 2015). The molecular correlates of the RRsensitive K 1 current may be TREK-2, TASK-3, or TRAAK homodimers, or heterodimers of the TREK subfamily (Braun et al, 2015;Blin et al, 2016;Lengyel et al, 2016). We found that in neurons derived from wild-type animals, A2764 strongly inhibited the background K 1 current in a subset of DRG neurons.…”

Formation of Functional Heterodimers by TREK-1 and TREK-2 Two-pore Domain Potassium Channel Subunits

“…Note Added in Proof-While this paper was under review, other authors have published results showing heteromerization of channels in the TREK K 2P subfamily (38,39). These studies reached the same conclusion by using different methods.…”

Fatty Acid Regulation of Voltage- and Ligand-Gated Ion Channel Function

“…Kim (2003) reviewed the main characteristics of the modulation of two-pore domain K + channels by FFA (TREK-1, TREK-2, and TRAAK). These channels, activated by GPCRs, stretch, pH, and PUFA, are broadly expressed in the nervous system where they control neuronal excitability (Lee et al, 2011; Liu et al, 2014; Blin et al, 2016). The effect of PUFA on TREK channels has profound physiological implications, since TREK-1 was shown to mediate the neuroprotection induced by PUFA (Lauritzen et al, 2000; Heurteaux et al, 2004; Noël et al, 2011; Liu et al, 2014).…”