ABSTRACT
In human liver, Ca(2+)-dependent changes in membrane K(+) permeability play a central role in coordinating functional interactions between membrane transport, metabolism, and cell volume. On the basis of the observation that K(+) conductance is partially sensitive to the bee venom toxin apamin, we aimed to assess whether small-conductance Ca(2+)-sensitive K(+) (SK(Ca)) channels are expressed endogenously and contribute to volume-sensitive K(+) efflux and cell volume regulation. We isolated a full-length 2,140-bp cDNA (hSK2) highly homologous to rat brain rSK2 cDNA, including the putative apamin-sensitive pore domain, from a human liver cDNA library. Identical cDNAs were isolated from primary human hepatocytes, human HuH-7 hepatoma cells, and human Mz-ChA-1 cholangiocarcinoma cells. Transduction of Chinese hamster ovary cells with a recombinant adenovirus encoding the hSK2-green fluorescent protein fusion construct resulted in expression of functional apamin-sensitive K(+) channels. In Mz-ChA-1 cells, hypotonic (15% less sodium glutamate) exposure increased K(+) current density (1.9 +/- 0.2 to 37.5 +/- 7.1 pA/pF; P < 0.001). Apamin (10-100 nM) inhibited K(+) current activation and cell volume recovery from swelling. Apamin-sensitive SK(Ca) channels are functionally expressed in liver and biliary epithelia and likely contribute to volume-sensitive changes in membrane K(+) permeability. Accordingly, the hSK2 protein is a potential target for pharmacological modulation of liver transport and metabolism through effects on membrane K(+) permeability.
