Calcium modulation of vascular smooth muscle ATP-sensitive K+ channels - Role of protein phosphatase-2B.
1019 - 1025.
ATP-sensitive K+ (K-ATP) channels are broadly distributed in the vasculature and regulate arterial tone. These channels are inhibited by intracellular ATP ([ATP],) and vasoconstrictor agents and can be activated by vasodilators. It is widely assumed that K-ATP, channels are insensitive to Ca2+, although regulation has not been examined in the intact cell where cytosolic regulatory processes may be important. Thus we investigated the effects of Ca2+ on whole-cell K-ATP current in rat aortic smooth muscle cells recorded in a physiological [ATP], and K+ gradient. Under control recording conditions, cells had a resting potential of approximate to -40 mV when bathed in 1.8 mmol/L Ca2+. The K-ATP channel inhibitor glibenclamide caused membrane depolarization (9 mV) and inhibited a small, time-independent background current. Reducing [ATP](i) from 3 to 0.1 mmol/L hyperpolarized cells to approximate to -60 mV and increased glibenclamide-sensitive current by 2- to 4-fold. Similar effects were observed when Ca2+ levels were decreased either externally or internally by increasing EGTA from 1 to 10 mmol/L. Dialysis with solutions containing different free [Ca2+](i) showed that K-ATP current was maximally activated at 10 nmol/L [Ca2+](i) and almost totally inhibited at 300 nmol/L. Moreover, under control conditions, when rat aortic smooth muscle cells were dialyzed with either cyclosporin A, FK-506, or calcineurin autoinhibitory peptide (structurally unrelated inhibitors of Ca2+-dependent protein phosphatase, type 2B), glibenclamide-sensitive currents were large and the resting potential was hyperpolarized by approximate to 20 to 25 mV. We report for the first time that K-ATP, channels can be modulated by Ca2+ at physiological [ATP](i) and conclude that modulation occurs via protein phosphatase type 2B.
|Title:||Calcium modulation of vascular smooth muscle ATP-sensitive K+ channels - Role of protein phosphatase-2B|
|Keywords:||calcium, K-ATP channel, protein phosphatase-2B, smooth muscle, whole-cell recording, RAT VENTRICULAR MYOCYTES, POTASSIUM CHANNELS, PORTAL-VEIN, AUTOINHIBITORY DOMAIN, CA2+ RELEASE, ION CHANNELS, KINASE-C, CELLS, RABBIT, ACTIVATION|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of) > Metabolism and Experimental Therapeutics
UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > UCL Medical School > Academic Centre of Medical Education
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