PKC-dependent regulation of Kv7.5 channels by the bronchoconstrictor histamine in human airway smooth muscle cells.

Kv7 potassium channels have recently been found to be expressed and functionally important for relaxation of airway smooth muscle. Previous research suggests that native Kv7 currents are inhibited following treatment of freshly isolated airway smooth muscle cells with bronchoconstrictor agonists, and in intact airways inhibition of Kv7 channels is sufficient to induce bronchiolar constriction. However, the mechanism by which Kv7 currents are inhibited by bronchoconstrictor agonists has yet to be elucidated. In the present study, native Kv7 currents in cultured human trachealis smooth muscle cells (HTSMCs) were observed to be inhibited upon treatment with histamine; inhibition of Kv7 currents was associated with membrane depolarization and an increase in cytosolic Ca²⁺ ([Ca²⁺]_cyt). The latter response was inhibited by verapamil, a blocker of L-type voltage-sensitive Ca²⁺ channels (VSCCs). Protein kinase C has been implicated as a mediator of bronchoconstrictor actions, although the targets of are not clearly established. We found that histamine treatment significantly and dose-dependently suppressed currents through overexpressed wild-type human Kv7.5 (hKv7.5) channels in cultured HTSMCs, and this effect was inhibited by the duanyu1531 inhibitor Ro-31-8220 (3 µM). The suppression of hKv7.5 currents corresponded with a duanyu1531-dependent increase in hKv7.5 channel phosphorylation. Knocking down or inhibiting or mutating hKv7.5 serine 441 to alanine, abolished the inhibitory effects of histamine on hKv7.5 currents. These findings provide the first evidence linking duanyu1531 activation to suppression of Kv7 currents, membrane depolarization, and Ca²⁺ influx via L-type VSCCs as a mechanism for histamine-induced bronchoconstriction.

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