Crossing subfamily borders: Mechanosensitive TREK‐1 and alkaline‐activated TASK‐4 form heterodimers with unique functional and pharmacological properties

Background and Purpose The tandem of two‐pore‐domain potassium (K 2P ) channels TREK‐1 and TASK‐4 are expressed in the heart and pancreatic beta‐cells. As TREK‐1 and TASK‐4 belong to distinct subfamilies with different functional hallmarks, heteromerization of these two channels was highly unexpected. However, due to their shared expression in these tissues and their involvement in congenital cardiac arrhythmias, the aim of this study was to probe for a possible formation of TREK‐1/TASK‐4 heterodimers. Experimental Approach Two‐electrode voltage‐clamp and inside‐out macropatch clamp recordings, together with immunohistochemistry and chemiluminescence‐based ELISA assays, were utilized to describe heteromerization of TREK‐1 and TASK‐4 channels and elucidate the characteristics of this heteromeric channel complex. Key Results Here, we show that the mechanosensitive TREK‐1 forms heteromeric channel complexes with the alkaline‐activated TASK‐4. The resulting heterodimers of these only remotely related channels have an enhanced temperature sensitivity, an altered pH dependence and regulation by extracellular sodium. Unlike TREK‐1, heteromeric TREK‐1/TASK‐4 channels are not inhibited via G s ‐coupled receptor activation, as the heterodimeric channels are not PKA sensitive. Strikingly, these novel heterodimeric channel complexes are characterized by a unique pharmacology. Conclusions and Implications The newly described heterodimerization across different K 2P channel families is of major relevance for drugs targeting TASK‐4 or TREK‐1. Their functional co‐expression in different tissues raises the possibility of developing drugs against cardiac arrhythmias and Type 2 diabetes by specifically targeting these unique heterodimeric channel complexes.