We isolated three novel 2P domain K+ channel. subunits from human. The first two subunits, TALK-1 and TALK-2, are distantly related to TASK-2, Their genes form a tight cluster of 25 kb on chromosome 6p21.1-p21.2, The corresponding channels produce quasi-instantaneous and non-inactivating currents that are activated at alkaline pHs, These currents are sensitive to Ba2+, quinine, quinidine, chloroform, halothane, and isoflurane but are not affected by TEA, 4-AP, Cs+, arachidonic acid, hypertonic solutions, agents activating protein kinases C and A, changes of internal Ca2+ concentrations, and by activation of G(i) and G(q) proteins. TALK-1 is exclusively expressed in the pancreas. TALK-2 is mainly expressed in the pancreas, but is also expressed at a lower level in liver, placenta, heart, and lung. We also cloned a third subunit, named hTHIK-2 which is present in many tissues with high levels again in the pancreas but which could not be functionally expressed.