Dexamethasone reduces airway epithelial Cl secretion by rapid non-genomic inhibition of KCNQ1, KCNN4 and KATP K channels.

Basolateral membrane K channels play a key role in basal and agonist stimulated Cl transport across airway epithelial cells by generating a favourable electrical driving force for Cl efflux. The K channel sub-types and molecular mechanisms of regulation by hormones and secretagoues are still poorly understood. Here we have identified the type of K channels involved in cAMP and Ca stimulated Cl secretion and uncovered a novel anti-secretory effect of dexamethasone mediated by inhibition of basolateral membrane K channels in a human airway cell model of 16HBE14o cells commonly used for ion transport studies. Dexamethasone produced a rapid inhibition of transepithelial chloride ion secretion under steady state conditions and after stimulation with cAMP agonist (forskolin) or a Ca mobilizing agonist (ATP). Our results show three different types of K channels are targeted by dexamethasone to reduce airway secretion, namely Ca-activated secretion via KCNN4 (KCa3.1) channels and cAMP-activated secretion via KCNQ1 (Kv7.1) and KATP (Kir6.1,6.2) channels. The down-regulation of KCNN4 and KCNQ1 channel activities by dexamethasone involves rapid non-genomic activation of PKCα and PKA signalling pathways, respectively. Dexamethasone signal transduction for PKC and PKA activation was demonstrated to occur through a rapid non-genomic pathway that did not implicate the classical nuclear receptors for glucocorticoids or mineralocorticoids but occurred via a novel signalling cascade involving sequentially a G-protein coupled receptor, PKC, adenylyl cyclase Type IV, cAMP, PKA and ERK1/2 activation. The rapid, non-genomic, effects of dexamethasone on airway epithelial ion transport and cell signalling introduces a new paradigm for glucocorticoid actions in lung epithelia which may serve to augment the anti-inflammatory activity of the steroid and enhance its therapeutic potential in treating airway hypersecretion in asthma and COPD.