Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release Academic Article uri icon

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abstract

  • The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αβγ heterotrimer responsible for energy homeostasis. Pharmacological inhibition of AMPK is regarded as a therapeutic strategy in some disease settings including obesity and cancer; however, the broadly used direct AMPK inhibitor compound C suffers from poor selectivity. We have discovered a dihydroxyquinoline drug (MT47-100) with novel AMPK regulatory properties, being simultaneously a direct activator and inhibitor of AMPK complexes containing the β1 or β2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the β2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of β2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by β1/β2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a β2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors.

authors

  • Scott, John W
  • Galic, Sandra
  • Graham, Kate L
  • Foitzik, Richard
  • Ling, Naomi XY
  • Dite, Toby A
  • Issa, Samah MA
  • Langendorf, Chris G
  • Weng, Qing Ping
  • Thomas, Helen E
  • Kay, Thomas W
  • Birnberg, Neal C
  • Steinberg, Gregory
  • Kemp, Bruce E
  • Oakhill, Jonathan S

publication date

  • June 2015

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