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Two-pore domain potassium channel (K_2P) channels produce background K⁺ conductance that control resting membrane potential and influence cell excitability. They are involved in functions as diverse as cell volume regulation, neuronal excitability, cardiac rhythm, apoptosis and fluid balance. Recently, K_2P have emerged as promising targets for the development of new classes of anesthetics, analgesics and antidepressants. However, we demonstrated that K_2P channels, and particularly THIK and TREK subfamilies, assemble and form active heterodimeric channels. We combined biochemistry, immunocytochemistry, FRET as well as electrophysiology to prove physical interaction among subunits. Interestingly, heterodimers exhibit unitary conductances, pharmacology and regulations different of those of the corresponding homodimers. 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.

Reference:
Blin, S, Ben Soussia, I, Kim, EJ, Brau, F, Kang, D, Lesage, F and Delphine Bichet.  Mixing and matching TREK/TRAAK subunits generate heterodimeric K_2P channels with unique properties.  Proc Natl Acad Sci USA 2016, 113(15): 4200-4205