Hypoxic and metabolic regulation of voltage-gated K+ channels in rat pulmonary artery smooth muscle cells.
Inhibition of voltage-gated K+ (Kv) channels by 4-aminopyridine (4-AP) depolarizes pulmonary artery (PA) smooth muscle cells, induces Ca(2+)-dependent action potentials and increases [Ca2+]i. Neither charybdotoxin, which blocks Ca(2+)-activated K+ channels, nor glibenclamide, which blocks ATP-sensitive K+ channels, has such effects on membrane potential (Em) and [Ca2+]i. Hypoxia reversibly decreases the 4-AP-sensitive KV currents (IK(V)) in PA myocytes. The resulting membrane depolarization caused by decreased IK(V) induces Ca(2+)-dependent action potentials and thereby raises [Ca2+]i. Thus, KV channel activity plays a critical role in: (a) regulating Em and [Ca2+]i under physiological conditions; and (b) sensing O2 alteration and transducing the hypoxic stimulus to changes of Em and [Ca2+]i. The metabolic inhibitors 2-deoxy-D-glucose (2-DOG; 10 mM) and carbonyl cyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP; 3-5 microM), the reducing agent reduced glutathione and inhibitors of cytochrome P-450, all mimic the effects of hypoxia on IK(V) and Em in PA myocytes. Furthermore, hypoxia and 2-DOG negligibly affect IK(V) and Em in mesenteric artery smooth muscle cells. These results suggest that hypoxia, perhaps via a localized reduction of ATP, triggers the block of KV channels and depolarizes PA myocytes. This blockade may also be mediated by a change in cellular redox status, perhaps via a conformational change of a haem- (or metal-) containing regulatory moiety that is attached to the channel protein.
Department of Medicine, University of Maryland School of Medicine, Baltimore 21201, USA.
X J
XJ
Yuan
M L
ML
Tod
L J
LJ
Rubin
M P
MP
Blaustein
D000818:Animals; D004594:Electrophysiology; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism*; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D051381:Rats
D015221:Potassium Channels