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K_Ca3.1 Ca²⁺Activated K⁺ Channels Regulate Human Airway Smooth Muscle Proliferation

¹ Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom; ² Department of Pharmacology, University of Melbourne, Parkville, Melbourne, Australia; ³ Department of Infection, Immunity and Inflammation, Institute for Lung Health, University of Leicester, Leicester, United Kingdom; and ⁴ Department of Anatomy and Cell Biology, University of Melbourne, Parkville, Melbourne, Australia

Correspondence and requests for reprints should be addressed to Dr. Malcolm Shepherd, Rm B3/23, GBRC Building, 120 University Avenue, University of Glasgow, Glasgow, UK G12 8QQ. E-mail: mcs9h{at}clinmed.gla.ac.uk

Airway smooth muscle cell hyperplasia contributes to airway remodeling and hyperreactivity 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 K_Ca3.1 in HASM cells and investigate its role in proliferation. Smooth muscle cells derived from human airways were grown in vitro and K_Ca3.1 channel expression was measured using Western blot, RT-PCR, and patch clamp electrophysiology. Pharmacologic inhibitors of the channel were used in assays of cellular proliferation, and flow cytometry was used to identify cell cycle regulation. HASM cells expressed K_Ca3.1 channel mRNA, protein, and activity with up-regulation evident after transforming growth factor- stimulation. Pharmacologic inhibition of K_Ca3.1 led to growth arrest in cells stimulated to proliferate with mitogens. These inhibitors did not cause cellular toxicity or induce apoptosis. We have demonstrated, for the first time, the expression of K_Ca3.1 channels in HASM cells. In addition, we have shown that K_Ca3.1 channels are important in HASM cell proliferation, making these channels a potential therapeutic target in airway remodeling.

Key Words: asthma • ion channels • cell cycle

CLINICAL RELEVANCE This novel description of the up-regulation and function of a potassium channel in human airway smooth muscle cell provides new insights into the changes in molecular regulation of key airway cells during proliferation.