Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy. Journal Article

Authors: Brueggemann, L. I.; Kakad, P. P.; Love, R. B.; Solway, J; Dowell, M. L.; Cribbs, L. L.; Byron, K. L.
Article Title: Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy.
Abstract: Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 muM), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 muM). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2-7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists.
Keywords: Humans; Molecular Pharmacology; Male; Animals; Aminopyridines; Anthracenes; Bronchoconstriction; Bronchodilator Agents; Calcium Channel Blockers; Carbamates; Guinea Pigs; Histamine; KCNQ Potassium Channels; Methacholine Chloride; Myocytes, Smooth Muscle; Patch-Clamp Techniques; Phenylenediamines; Pyrazoles; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Sulfonamides; Verapamil
Journal Title: American Journal of Physiology - Lung Cellular Molecular Physiology
Volume: 302
Issue: 1
ISSN: 1522-1504
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 120
End Page: 132
Language: English
Notes: ID: 12102; Record Owner: From MEDLINE, a database of the U.S. National Library of Medicine.; Status: MEDLINE; Publishing Model: Journal available in: Print-Electronic Citation processed from: Internet; NLM Journal Code: dko, 100901229; CAS Registry/EC Number/Name of Substance: 0 (10,10-bis(4-pyridinylmethyl)-9(10H)-anthracenone). 0 (Aminopyridines). 0 (Anthracenes). 0 (Bronchodilator Agents). 0 (Calcium Channel Blockers). 0 (Carbamates). 0 (KCNQ Potassium Channels). 0 (Phenylenediamines). 0 (Pyrazoles). 0 (Sulfonamides). 150812-12-7 (D 23129). 169590-42-5 (celecoxib). 51-45-6 (Histamine). 52-53-9 (Verapamil). 56995-20-1 (flupirtine). 62-51-1 (Methacholine Chloride).; Grant Number: R01 HL089564 (United States NHLBI NIH HHS), R01 HL089564-04 (United States NHLBI NIH HHS); Electronic Date of Publication: 20110930; Entry Date: 20120222