Mixing and matching TREK/TRAAK subunits generate heterodimeric K 2P 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.