Tolerance for ATP-insensitive K(ATP) channels in transgenic mice
J C Koster1, A Knopp, T P Flagg
1Department of Cell Biology, Washington University School of Medicine, St Louis, MO, USA.
Circulation Research
|November 22, 2001
Summary
Altered cardiac ATP-sensitive potassium (KATP) channels in mice showed reduced ATP sensitivity but maintained normal heart function. This suggests cardiac KATP channels tolerate reduced ATP sensitivity, unlike those in pancreatic beta-cells.
Area of Science:
- Cardiovascular Physiology
- Molecular Cardiology
- Ion Channel Biology
Background:
- Sarcolemmal ATP-sensitive potassium (KATP) channels play a crucial role in cardiac function.
- Understanding their regulation and sensitivity to ATP is vital for cardiac health.
Purpose of the Study:
- To investigate the functional consequences of reduced ATP sensitivity in cardiac KATP channels.
- To compare the effects of altered KATP channel function in the heart versus pancreatic beta-cells.
Main Methods:
- Generation of transgenic mice expressing GFP-tagged Kir6.2 subunits with reduced ATP sensitivity under the cardiac alpha-myosin heavy chain promoter.
- Electrocardiography in conscious animals.
- Excised membrane patch-clamp and whole-cell voltage-clamp electrophysiology on isolated myocytes.
- Assessment of KATP channel density and conductance.
Main Results:
- Transgenic mice exhibited normal fertility and overall health, with a modest decrease in mean heart rate.
- Cardiac KATP channels in transgenic mice showed significantly reduced sensitivity to ATP inhibition (K(1/2) = 2.7 mmol/L vs. 51 micromol/L in controls).
- Counterintuitively, KATP channel density was reduced ~4-fold, leading to lower overall KATP conductance, with no observed action potential shortening.
Conclusions:
- Cardiac KATP channels demonstrate a remarkable tolerance for reduced ATP sensitivity.
- Altered cardiac KATP channel function does not impair cardiac electrical activity under basal conditions.
- This highlights differential roles and regulatory mechanisms of KATP channels in cardiac myocytes versus pancreatic beta-cells.
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