SUMMARY
Pancreatic β-cells use phosphoenolpyruvate (PEP) cycling by pyruvate kinase (PK) to signal appropriate insulin secretion. Here, we show that the isoforms of PK, together with the PEP generated by mitochondrial PEP carboxykinase (PCK2), endow ATP-sensitive K+ (KATP) channels with nutrient sensitivity and specificity. Glucose-dependent regulation of the KATP channel is locally controlled by the allosterically tunable PKm2 isoform, which is remarkable considering that PKm1 accounts for >90% of cellular activity and is sufficient for KATP closure in the channel microcompartment. Mitochondrial signaling to the plasma membrane, which determines the β-cell response to amino acids, depends on both PCK2 and PKm1 to close KATP channels. In addition to these membrane depolarizing “on-switches,” we identified a mitochondrial PEP-dependent “off-switch” that regulates the length of depolarization. This back and forth communication between the KATP channel and mitochondria via highly compartmentalized PEP metabolism controls the oscillatory cycle regulating insulin secretion.
Competing Interest Statement
The authors have declared no competing interest.