Adisrupter of actin microfilaments impairs sulfonylurea-inhibitory
gating of cardiac katp channels.
Brady, Peter A., Alexey E. Alekseev, Luba A. Aleksandrova, Luis A.
Gomez, and Andre Terzic.
Division of Cardiovascular Diseases, Department of Medicine and
Pharmacology, Mayo Clinic, Mayo Foundation, Rochester, MN 55905
APStracts 3:0413H, 1996.
The efficacy with which sulfonylureas inhibit cardiac ATP-sensitive K+
(KATP) channels is reduced during metabolic compromise and cellular
contracture. Disruption of the actin-microfilament network, which
occurs under similar conditions, reduces the sensitivity of the
channel towards intracellular ATP. To investigate whether a disrupter
of actin-microfilaments could also affect the responsiveness of the
KATP channel to sulfonylureas, single channel currents were measured
in the inside-out configuration of excised patches from guinea-pig
ventricular myocytes. Treatment of the internal side of patches with
DNase I (100 [mu]g/ml), which forms complexes with G-actin and
prevents actin-filament formation, antagonized sulfonylurea-induced
inhibition of KATP channels which was coupled with a loss of
sensitivity to ATP. The apparent Kd and Hill coefficient for the
inhibitory effect of glyburide, a prototype sulfonylurea, on KATP
channel opening were respectively 0.13 [mu]M and 0.95 prior to and
2.7 [mu]M and 0.98, following DNase-treatment. DNase did not alter
intraburst kinetic properties of the channel. When denatured or co
-incubated with purified actin (200 [mu]g/ml), DNase I no longer
decreased glyburide-induced channel inhibition. This suggests that
sulfonylurea-inhibitory gating of cardiac KATP channels may also be
regulated through a mechanism involving sub-sarcolemmal actin
-microfilament networks.
Received 7 August 1996; accepted in final form 13 September 1996.
APS Manuscript Number H717-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996