High glucose regulates the activity of cardiac sarcolemmal ATP-Sensitive K+ channels via 1,3-bisphosphoglycerate: a novel link between cardiac membrane excitability and glucose metabolism

Because we were interested in assessing glucose-mediated regulation of the activity of sarcolemmal ATP-sensitive K+ channels (KATP channels) (which are closed by physiological levels of intracellular ATP and serve to couple intracellular metabolism with the membrane excitability in the heart) during ischemia, we performed experiments designed to test whether high extracellular glucose would have effects on sarcolemmal KATP channels per se. Surprisingly, we found that high extracellular glucose (50 mmol/l) activates sarcolemmal KATP channels in isolated guinea pig cardiomyocytes. To activate KATP channels, glucose had to be transported into cardiomyocytes and subjected to glycolysis. The activation of these channels was independent of ATP production and intracellular ATP levels. The effect of glucose on sarcolemmal KATP channels was mediated by the catalytic activity of glyceraldehyde-3-phosphate dehydrogenase and consequent generation of 1,3-bisphosphoglycerate. The 1,3-bisphosphoglycerate (20 mmol/l), an intermediate product of glycolysis, directly targeted and activated KATP channels, despite physiological levels of intracellular ATP (5 mmol/l). We conclude that glucose, so far exclusively viewed as a metabolic fuel in the heart important only during ischemia/hypoxia, may serve a signaling role in the nonstressed myocardium by producing an agent that regulates cardiac membrane excitability independently of high-energy phosphates.