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

Cell Rep. 2023 Apr 25;42(4):112394. doi: 10.1016/j.celrep.2023.112394. Epub 2023 Apr 13.


The ATP-sensitive K+ (KATP) channel is a key regulator of hormone secretion from pancreatic islet endocrine cells. Using direct measurements of KATP 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 KATP channels on the plasma membrane. The two ATP-consuming enzymes of upper glycolysis, glucokinase and phosphofructokinase, generate ADP that activates KATP. 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 KATP-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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenosine Diphosphate / metabolism
  • Animals
  • Cell Membrane* / enzymology
  • Cell Membrane* / metabolism
  • Electrophysiology
  • Glucagon-Secreting Cells* / metabolism
  • Glyceraldehyde-3-Phosphate Dehydrogenases / metabolism
  • Glycolysis*
  • Humans
  • Insulin-Secreting Cells* / metabolism
  • KATP Channels / metabolism
  • Lactate Dehydrogenases / metabolism
  • Mice
  • Patch-Clamp Techniques
  • Phosphofructokinases / metabolism


  • KATP Channels
  • Lactate Dehydrogenases
  • Glyceraldehyde-3-Phosphate Dehydrogenases
  • Adenosine Diphosphate
  • Phosphofructokinases