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, Colin G. Nichols

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

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 α-myosin heavy chain promoter. Four founder mice were isolated, and both founders and progeny were all apparently normal and fertile. Electrocar-diograms 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 ≊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 β-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.

Original languageEnglish
Pages (from-to)1022-1029
Number of pages8
JournalCirculation research
Volume89
Issue number11
DOIs
StatePublished - Nov 23 2001

Keywords

  • Electrocardiogram
  • K
  • K current
  • Transgenic

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