© 2000 American Heart Association, Inc.
Cellular Biology |
Calcium Modulation of Vascular Smooth Muscle ATP-Sensitive K+ Channels
Role of Protein Phosphatase-2B
From the Centre for Clinical Pharmacology, Department of Medicine, University College London, UK.
Correspondence to Dr Lucie H. Clapp, Centre of Clinical Pharmacology, Department of Medicine, University College London, 5 University St, London WC1E 6JJ, UK. E-mail l.clapp{at}ucl.ac.uk
Abstract—ATP-sensitive
K+ (KATP) channels
are broadly distributed in the vasculature and regulate arterial tone.
These channels are inhibited by intracellular ATP
([ATP]i) and vasoconstrictor agents and can be
activated by vasodilators. It is widely assumed that
KATP 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
KATP current in rat aortic smooth muscle cells
recorded in a physiological [ATP]i and
K+ gradient. Under control recording
conditions, cells had a resting potential of 
-40 mV when bathed in
1.8 mmol/L Ca2+. The
KATP 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 -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
KATP 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 20 to 25 mV. We report for the first
time that KATP channels can be modulated by
Ca2+ at physiological
[ATP]i and conclude that modulation occurs via
protein phosphatase type
2B.
Key Words: calcium • KATP channel • protein phosphatase-2B • smooth muscle • whole-cell recording
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