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Expression of intermediate-conductance, Ca²⁺-activated K⁺ channel (KCNN4) in H441 human distal airway epithelial cells

Lung Membrane Transport Group, Division of Maternal and Child Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom

Submitted 22 February 2006 ; accepted in final form 30 May 2006

Electrophysiological studies of H441 human distal airway epithelial cells showed that thapsigargin caused a Ca²⁺-dependent increase in membrane conductance (G_Tot) and hyperpolarization of membrane potential (V_m). These effects reflected a rapid rise in cellular K⁺ conductance (G_K) and a slow fall in amiloride-sensitive Na⁺ conductance (G_Na). The increase in G_Tot was antagonized by Ba²⁺, a nonselective K⁺ channel blocker, and abolished by clotrimazole, a KCNN4 inhibitor, but unaffected by other selective K⁺ channel blockers. Moreover, 1-ethyl-2-benzimidazolinone (1-EBIO), which is known to activate KCNN4, increased G_K with no effect on G_Na. RT-PCR-based analyses confirmed expression of mRNA encoding KCNN4 and suggested that two related K⁺ channels (KCNN1 and KCNMA1) were absent. Subsequent studies showed that 1-EBIO stimulates Na⁺ transport in polarized monolayers without affecting intracellular Ca²⁺ concentration ([Ca²⁺]_i), suggesting that the activity of KCNN4 might influence the rate of Na⁺ absorption by contributing to G_K. Transient expression of KCNN4 cloned from H441 cells conferred a Ca²⁺- and 1-EBIO-sensitive K⁺ conductance on Chinese hamster ovary cells, but this channel was inactive when [Ca²⁺]_i was <0.2 µM. Subsequent studies of amiloride-treated H441 cells showed that clotrimazole had no effect on V_m despite clear depolarizations in response to increased extracellular K⁺ concentration ([K⁺]_o). These findings thus indicate that KCNN4 does not contribute to V_m in unstimulated cells. The present data thus establish that H441 cells express KCNN4 and highlight the importance of G_K to the control of Na⁺ absorption, but, because KCNN4 is quiescent in resting cells, this channel cannot contribute to resting G_K or influence basal Na⁺ absorption.

airway Na⁺ transport; cloning; Chinese hamster ovary cell expression; 1-ethyl-2-benzimidazolinone

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