Activation of K+ channels induces apoptosis in vascular smooth muscle cells.
Intracellular K+ plays an important role in controlling the cytoplasmic ion homeostasis for maintaining cell volume and inhibiting apoptotic enzymes in the cytosol and nucleus. Cytoplasmic K+ concentration is mainly regulated by K+ uptake via Na+-K+-ATPase and K+ efflux through K+ channels in the plasma membrane. Carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), a protonophore that dissipates the H+ gradient across the inner membrane of mitochondria, induces apoptosis in many cell types. In rat and human pulmonary artery smooth muscle cells (PASMC), FCCP opened the large-conductance, voltage- and Ca2+-sensitive KK+ (maxi-K) channels, increased K+ currents through maxi-K channels [I(K(Ca))], and induced apoptosis. Tetraethylammonia (1 mM) and iberiotoxin (100 nM) decreased I(K(Ca)) by blocking the sarcolemmal maxi-K channels and inhibited the FCCP-induced apoptosis in PASMC cultured in media containing serum and growth factors. Furthermore, inhibition of K+ efflux by raising extracellular K+ concentration from 5 to 40 mM also attenuated PASMC apoptosis induced by FCCP and the K+ ionophore valinomycin. These results suggest that FCCP-mediated apoptosis in PASMC is partially due to an increase of maxi-K channel activity. The resultant K+ loss through opened maxi-K channels may serve as a trigger for cell shrinkage and caspase activation, which are major characteristics of apoptosis in pulmonary vascular smooth muscle cells.
Division of Pulmonary and Critical Care Medicine, UCSD Medical Center, 200 W. Arbor Dr., San Diego, CA 92103-8382, USA.
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Krick
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Sweeney
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Kim
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Yuan
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005456:Fluorescent Dyes; D007425:Intracellular Membranes / Q000187:drug effects / Q000378:metabolism; D007476:Ionophores / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008564:Membrane Potentials / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000493:pharmacokinetics; D015221:Potassium Channels / Q000378:metabolism*; D024681:Potassium Channels, Calcium-Activated; D011651:Pulmonary Artery / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020112:Rhodamine 123; D012508:Sarcolemma / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology; D014634:Valinomycin / Q000494:pharmacology
D005456:Fluorescent Dyes; D007476:Ionophores; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D015221:Potassium Channels; D024681:Potassium Channels, Calcium-Activated; D020112:Rhodamine 123; D014634:Valinomycin; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; D019789:Tetraethylammonium; C064719:iberiotoxin; D011188:Potassium; D002118:Calcium