2019

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Published:  31 December 2019

For further discussion of some of the publications below as well as additional articles that we publish on our website and other locations that are not peer-reviewed publications, please visit our blog. You may also be interested in our webinar series and posters.

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

Published:  19 July 2019

Darina Hynes (SEKISUI XenoTech EU Business Development Manager), Brian J.Harvey

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 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 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 Gi-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.

Minding Your Binding: Plasma Protein Binding Potential Study Now Available in US and Japan Labs

Published:  15 April 2019

Madison Knapp, Andrea Wolff, Dr. Joanna Barbara

Plasma Brotein Binding potential is an important part of safety considerations for a drug candidate, and data can affect dosing considerations in clinical trials. PPB studies, now available on our KC campus, use Rapid Equilibrium Dialysis to determine fraction unbound so you can reliably measure free drug concentration for therapeutic effect. Read more about the features and benefits of this updated service...