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Circulation Research. 2001
Published online before print October 18, 2001, doi: 10.1161/hh2301.100342
A more recent version of this article appeared on November 23, 2001
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Submitted on May 21, 2001
Revised on October 8, 2001
Accepted on October 8, 2001

Tolerance for ATP-Insensitive KATP Channels in Transgenic Mice

Joseph C. Koster , Andreas Knopp , Thomas P. Flagg , Kamelia P. Markova , Qun Sha , Decha Enkvetchakul , Tetsuo Betsuyaku , Kathryn A. Yamada , and Colin G. Nichols *

From the Department of Cell Biology and Physiology (J.C.F., T.P.F., K.P.M., Q.S., D.E., C.G.N.), Washington University School of Medicine, St Louis, Mo; the Institut fur Physiologie (A.K.), Abteilung Herz-Kreislauf-Physiologie, Friedrich-Schiller-Universitat Jena, Germany; and the Cardiovascular Division (T.B., K.A.Y.), Department of Medicine, Washington University School of Medicine, St Louis, Mo.

* To whom correspondence should be addressed. E-mail: cnichols{at}cellbio.wustl.edu.

To examine the role of sarcolemmal KATP channels in cardiac function, we generated transgenic mice expressing GFP-tagged Kir6.2 subunits with reduced ATP sensitivity under control of the cardiac {alpha}-myosin heavy chain promoter. Four founder mice were isolated, and both founders and progeny were all apparently normal and fertile. Electrocardiograms from conscious animals also appeared normal, although mean 24-hour heart rate was approximately 10% lower in transgenic animals compared with littermate controls. In excised membrane patches, KATP channels were very insensitive to inhibitory ATP: mean K1/2 ([ATP] causing half-maximal inhibition) was 2.7 mmol/L in high-expressing line 4 myocytes, compared with 51 µmol/L in littermate control myocytes. Counterintuitively, KATP channel density was {approx}4-fold lower in transgenic membrane patches than in control. This reduction of total KATP conductance was confirmed in whole-cell voltage-clamp conditions, in which KATP was activated by metabolic inhibition. KATP conductance was not obvious after break-in of either control or transgenic myocytes, and there was no action potential shortening in transgenic myocytes. In marked contrast to the effects of expression of similar transgenes in pancreatic ß-cells, these experiments demonstrate a profound tolerance for reduced ATP sensitivity of cardiac KATP channels and highlight differential effects of channel activity in the electrical activity of the 2 tissues.
Key words: K+ current • KATP • transgenic • electrocardiogram




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