The protein IsK is a dual activator of K⁺ and CI^- channels

THE protein IsK (M14,500) is present in epithelial cells¹, heart^2,3, uterus⁴ and lymphocytes⁵ and induces slowly activating K⁺ currents when expressed in Xenopus oocytes¹. The finding that mutations of its single transmembrane segment altered channel gating⁶ or selectivity⁷ has suggested that IsK is a channel-forming protein. But IsK does nof exhibit the K⁺ channel hallmarks⁸ (a conserved K⁺ selective pore (H5) flanked by either six^9-11 or two^12,13 membrane-spanning regions). Here we report that IsK expression in Xenopus oocytes also induces a Cl^- selective current very similar to the Cl^- current produced by phospholemman expression¹⁴ and with biophysical, pharmacological and regulation characteristics very different from those of the IsK-induced K⁺ channel activity. IsK mutagenesis identifies amino- and carboxy-terminal domains as critical for the induction of Cl^- and K⁺ channel activities, respectively. Our data lead to a model in which the IsK protein (now called IsK, Cl) acts as a potent activator of endogenous and otherwise silent K⁺ or Cl^- channels.