Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release

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

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34 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)705-711
Number of pages7
JournalChemistry and Biology
Volume22
Issue number6
DOIs
Publication statusPublished - 2015

Cite this

Scott, J. W., Galic, S., Graham, K. L., Foitzik, R., Ling, N. X. Y., Dite, T. A., Issa, S. M. A., Langendorf, C. G., Weng, Q. P., Thomas, H. E., Kay, T. W., Birnberg, N. C., Steinberg, G. R., Kemp, B. E., & Oakhill, J. S. (2015). Inhibition of AMP-activated protein kinase at the allosteric drug-binding site promotes islet insulin release. Chemistry and Biology, 22(6), 705-711. https://doi.org/10.1016/j.chembiol.2015.05.011