Heteromerization of alkaline-sensitive two-pore domain potassium channels

Two-pore domain (K2P) potassium channels are active as dimers. They produce inhibitory currents regulated by a variety of stimuli. Among them, TALK1, TALK2 and TASK2 form a subfamily of structurally related K2P channels stimulated by extracellular alkalosis. The human genes encoding them are clustered on chromosomal region 6p21. They are expressed in different tissues including the pancreas. By analyzing single cell transcriptomic data, we show that these channels are co-expressed in insulin-secreting pancreatic β cells. By different approaches we show that they form functional heterodimers. Heteromerization of TALK2 with TALK1 or with TASK2 endorses TALK2 with sensitivity to extracellular alkalosis in the physiological range. The association of TASK2 with TALK1 and TALK2 increases their unitary conductance. These results provide a new example of heteromerization in the K2P channel family expanding the range of their potential physiological and pathophysiological roles.