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.
- K current