title: KCa3.1 Ca2+ activated K+ channels regulate human airway smooth muscle proliferation.
abstract: 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(Ca)3.1 in HASM cells and investigate its role in proliferation. Smooth muscle cells derived from human airways were grown in vitro and K(Ca)3.1 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(Ca)3.1 channel mRNA, protein, and activity with up-regulation evident after transforming growth factor-beta stimulation. Pharmacologic inhibition of K(Ca)3.1 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(Ca)3.1 channels in HASM cells. In addition, we have shown that K(Ca)3.1 channels are important in HASM cell proliferation, making these channels a potential therapeutic target in airway remodeling.
authors.affiliation: Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, United Kingdom. mcs9h@clinmed.gla.ac.uk
authors.forename: Malcolm C
authors.initials: MC
authors.lastname: Shepherd
authors.forename: S Mark
authors.initials: SM
authors.lastname: Duffy
authors.forename: Trudi
authors.initials: T
authors.lastname: Harris
authors.forename: Glenn
authors.initials: G
authors.lastname: Cruse
authors.forename: Michael
authors.initials: M
authors.lastname: Schuliga
authors.forename: Chris E
authors.initials: CE
authors.lastname: Brightling
authors.forename: Craig B
authors.initials: CB
authors.lastname: Neylon
authors.forename: Peter
authors.initials: P
authors.lastname: Bradding
authors.forename: Alastair G
authors.initials: AG
authors.lastname: Stewart
mesh_terms: D002118:Calcium / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009130:Muscle, Smooth / Q000166:cytology* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012137:Respiratory System / Q000166:cytology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D011188:Potassium; D002118:Calcium