A plasma membrane-associated glycolytic metabolon is functionally coupled to KATP channels in pancreatic α and β cells from humans and mice

Abstract

The ATP-sensitive K⁺ (K_ATP) channel is a key regulator of hormone secretion from pancreatic islet endocrine cells. Using direct measurements of K_ATP channel activity in pancreatic β cells and the lesser-studied α cells, from both humans and mice, we provide evidence that a glycolytic metabolon locally controls K_ATP channels on the plasma membrane. The two ATP-consuming enzymes of upper glycolysis, glucokinase and phosphofructokinase, generate ADP that activates K_ATP. Substrate channeling of fructose 1,6-bisphosphate through the enzymes of lower glycolysis fuels pyruvate kinase, which directly consumes the ADP made by phosphofructokinase to raise ATP/ADP and close the channel. We further show the presence of a plasma membrane-associated NAD⁺/NADH cycle whereby lactate dehydrogenase is functionally coupled to glyceraldehyde-3-phosphate dehydrogenase. These studies provide direct electrophysiological evidence of a K_ATP-controlling glycolytic signaling complex and demonstrate its relevance to islet glucose sensing and excitability.

Keywords: CP: Metabolism; K(ATP) channel; glycolysis; glycolytic metabolon; inside-out excised patch clamp; metabolic compartmentation; pyruvate kinase.