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.
Krick
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Division of Pulmonary and Critical Care Medicine, UCSD Medical Center, 200 W. Arbor Dr., San Diego, CA 92103-8382, USA.
Platoshyn
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Sweeney
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M
Kim
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Yuan
J X
JX
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