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

• Published in: Cell reports (Cambridge) Vol. 42; no. 4; p. 112394
• Main Authors: Ho, Thuong, Potapenko, Evgeniy, Davis, Dawn B., Merrins, Matthew J.
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 25.04.2023; Elsevier
• Subjects: CP: Metabolism; glycolysis; glycolytic metabolon; inside-out excised patch clamp; KATP channel; metabolic compartmentation; pyruvate kinase; metabolic compartmentation; glycolytic metabolon; CP: Metabolism; pyruvate kinase; glycolysis; KATP channel; inside-out excised patch clamp
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.112394

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. [Display omitted] •KATP channels are regulated by a glycolytic metabolon on the plasma membrane•Substrate channeling occurs between the consecutive enzymes of glycolysis•Upper glycolysis produces ADP that is used directly by lower glycolysis to make ATP•LDH and GADPH facilitate a plasma membrane-associated NAD+/NADH redox cycle Ho et al. provide evidence that glycolytic enzymes, including lactate dehydrogenase, form a plasma membrane-associated metabolon with intrinsic ATP/ADP and NAD+/NADH cycles. The subcellular location of this complex allows both ATP-consuming and ATP-producing enzymes to locally control the ATP-sensitive K+ channel in human and mouse pancreatic α and β cells.