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(Circulation Research. 2001;89:1022.)
© 2001 American Heart Association, Inc.

Cellular Biology

Tolerance for ATP-Insensitive K_ATP Channels in Transgenic Mice

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

Correspondence to Colin G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Ave, St Louis, MO 63110. E-mail cnichols{at}cellbio.wustl.edu

To examine the role of sarcolemmal K_ATP channels in cardiac function, we generated transgenic mice expressing GFP-tagged Kir6.2 subunits with reduced ATP sensitivity under control of the cardiac -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, K_ATP channels were very insensitive to inhibitory ATP: mean K_1/2 ([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, K_ATP channel density was 4-fold lower in transgenic membrane patches than in control. This reduction of total K_ATP conductance was confirmed in whole-cell voltage-clamp conditions, in which K_ATP was activated by metabolic inhibition. K_ATP 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 K_ATP channels and highlight differential effects of channel activity in the electrical activity of the 2 tissues.

Key Words: K⁺ current • K_ATP • transgenic • electrocardiogram

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