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

Publication date: Available online 19 July 2019Source: SteroidsAuthor(s): Darina Hynes, Brian J. HarveyAbstractBasolateral 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 Ca2+ 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 Ca2+ mobilizing agonist (ATP). Our results show three different types of K+ channels are targeted by dexamethasone to reduce airway secretion, namely Ca2+-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 PKCĪ± 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 th...
Source: Steroids - Category: Drugs & Pharmacology Source Type: research