K ATP channel activity and slow oscillations in pancreatic beta cells are regulated by mitochondrial ATP production

• Autores: Corradi, Jeremias; Thompson, Benjamin; Fletcher, Patrick A.; Bertram, Richard; Sherman, Arthur S.; Satin, Leslie S.
• Año de publicación: 2023
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: DIABETES; PATCH-CLAMP; BETA CELLS
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Pancreatic beta cells secrete insulin in response to plasma glucose. The ATP-sensitive potassium channel (KATP) links glucose metabolism to islet electrical activity in these cells by responding to increased cytosolic [ATP]/[ADP]. It was recently proposed that pyruvate kinase (PK) in close proximity to beta cell KATP locally produces the ATP that inhibits KATP activity. This proposal was largely based on the observation that applying phosphoenolpyruvate (PEP) and ADP to the cytoplasmic side of excised inside-out patches inhibited KATP. To test the relative contributions of local vs. mitochondrial ATP production, we recorded KATP activity using mouse beta cells and INS-1 832/13 cells. In contrast to prior reports, we could not replicate inhibition of KATP activity by PEP + ADP. However, when the pH of the PEP solutions was not corrected for the addition of PEP, strong channel inhibition was observed as a result of the well-known action of protons to inhibit KATP. In cell-attached recordings, perifusing either a PK activator or an inhibitor had little or no effect on KATP channel closure by glucose, further suggesting that PK is not an important regulator of KATP. In contrast, addition of mitochondrial inhibitors robustly increased KATP activity. Finally, by measuring the [ATP]/[ADP] responses to imposed calcium oscillations in mouse beta cells, we found that oxidative phosphorylation could raise [ATP]/[ADP] even when ADP was at its nadir during the burst silent phase, in agreement with our mathematical model. These results indicate that ATP produced by mitochondrial oxidative phosphorylation is the primary controller of KATP in pancreatic beta cells
Fil: Corradi, Jeremias. University of Michigan; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina
Fil: Thompson, Benjamin. University of Michigan; Estados Unidos
Fil: Fletcher, Patrick A.. National Institutes of Health; Estados Unidos
Fil: Bertram, Richard. Florida State University; Estados Unidos
Fil: Sherman, Arthur S.. National Institutes of Health; Estados Unidos
Fil: Satin, Leslie S.. University of Michigan; Estados Unidos