Inhibition of AMP-Activated Protein Kinase at the Allosteric Drug-Binding Site Promotes Islet Insulin Release.
Chem Biol
; 22(6): 705-11, 2015 Jun 18.
Article
en En
| MEDLINE
| ID: mdl-26091167
ABSTRACT
The AMP-activated protein kinase (AMPK) is a metabolic stress-sensing αßγ 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 ß1 or ß2 isoform, respectively. Allosteric inhibition by MT47-100 was dependent on the ß2 carbohydrate-binding module (CBM) and determined by three non-conserved CBM residues (Ile81, Phe91, Ile92), but was independent of ß2-Ser108 phosphorylation. Whereas MT47-100 regulation of total cellular AMPK activity was determined by ß1/ß2 expression ratio, MT47-100 augmented glucose-stimulated insulin secretion from isolated mouse pancreatic islets via a ß2-dependent mechanism. Our findings highlight the therapeutic potential of isoform-specific AMPK allosteric inhibitors.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Proteínas Quinasas Activadas por AMP
/
Hidroxiquinolinas
/
Insulina
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Chem Biol
Asunto de la revista:
BIOLOGIA
/
BIOQUIMICA
/
QUIMICA
Año:
2015
Tipo del documento:
Article