Published ahead of print on June 21, 2007, doi:10.1165/rcmb.2006-0358OC Am. J. Respir. Cell Mol. Biol., Volume 37, Number 5, November 2007, 525-531 A more recent version of this article appeared on November 1, 2007
Submitted on September 22, 2006 KCa3.1 Ca2+ Activated K+ Channels Regulate Human Airway Smooth Muscle ProliferationMalcolm C Shepherd1*,1 Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK, United Kingdom; Department of Pharmacology, University of Melbourne, Melbourne, Vic, Australia, 2 Department of Infection, Immunity and Inflammation, University of Leicester, Institute for Lung Health, Leicester, UK, United Kingdom, 3 Department of Pharmacology, University of Melbourne, Melbourne, Vic, Australia, 4 Department of Anatomy and Cell Biology, University of Melbourne, Melbourne, Vic, Australia * To whom correspondence should be addressed. E-mail: mcs9h{at}clinmed.gla.ac.uk.
Rationale: Airway smooth muscle cell hyperplasia contributes to airway remodeling and hyper-reactivity characteristic of asthma. Changes to potassium channel activity in proliferating human airway smooth muscle (HASM) cells have been described, but no regulatory role in proliferation has been attributed to them. We sought to investigate the expression of the intermediate conductance calcium-activated potassium channel KCa3.1 in HASM cells and investigate its role in proliferation. Methods: Smooth muscle cells derived from human airways were grown in vitro and KCa3.1 channel expression was measured using Western blot, RT-PCR and patch clamp electrophysiology. Pharmacological inhibitors of the channel were used in assays of cellular proliferation and flow cytometry was used to identify cell cycle regulation. Results: HASM cells expressed KCa3.1 channel mRNA, protein and activity with up-regulation evident after TGF
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stimulation. Pharmacological inhibition of KCa3.1 led to growth arrest in cells stimulated to proliferate with mitogens. These inhibitors did not cause cellular toxicity or induce apoptosis. Conclusion: We have demonstrated, for the first time, the expression of KCa3.1 channels in HASM cells. In addition, we have shown KCa3.1 channels are important in HASM cell proliferation, making these channels a potential therapeutic target in airway remodeling.
