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Mixing and matching TREK/TRAAK subunits generate heterodimeric K2P channels with unique properties

Significance Nearly 350 human genes encode ion channels. Posttranscriptional (alternative splicing, editing, and alternative translation initiation) and posttranslational mechanisms (glycosylation, phosphorylation) further increase diversity. For multimeric channels, various heteromeric combinations may raise the number of ion channels to thousands. Here, we show that mixing and matching TWIK1-related K+ (TREK)/Twik-related acid-arachidonic activated K+ channel (TRAAK) subunits generate tens of different channels. Heterodimeric combinations have properties different from those of the corresponding homodimers, including single-channel behavior, regulation by kinases, and sensitivity to pharmacological agents. These results imply that any excitable cell can adjust its response to neurotransmitters by simply modulating the ratio of expressed TREK/TRAAK subunits. These results also imply that heteromerization has to be considered when analyzing in vivo functions of these channels but also when screening new potential therapeutic drugs. 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.