MOLECULAR-BASIS OF I-SK PROTEIN-REGULATION BY OXIDATION OR CHELATION

Slowly activating I-sK channels were expressed in Xenopus oocytes and exposed to oxidative agents. Oxidative treatment reduced the resulting current I-sK, while no inhibition was observed for I-sK protein mutan ts carrying a Ser mutation instead of a highly conserved Cys residue i n the intracellular domain. In contrast, Hg2+, which may not only oxid ize thiol groups but also form chelates with dibasic amino acids, caus ed a use-dependent, positive regulation of I-sK. This effect was rever sed in an I-sK protein mutant with a deletion in the extracellular dom ain. These data suggest opposite effects of peroxides and Hg2+ on I-sK , a peroxide-mediated I-sK inhibition by intracellular oxidation and a Hg2+-mediated I-sK increase, caused by extracellular Hg2+ chelation o f the I-sK protein.