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.
The AMP-activated protein kinase (AMPK) αβγ heterotrimer regulates cellular energy homeostasis with tissue-specific isoform distribution. Small-molecule activation of skeletal muscle α2β2 AMPK complexes may prove a valuable treatment strategy for type 2 diabetes and insulin resistance. Herein, we report the small-molecule SC4 is a potent, direct AMPK activator that preferentially activates α2 complexes and stimulates skeletal muscle glucose uptake. In parallel with the term secretagog, we propose "importagog" to define a substance that induces or augments cellular uptake of another substance. Three-dimensional structures of the glucose importagog SC4 bound to activated α2β2γ1 and α2β1γ1 complexes reveal binding determinants, in particular a key interaction between the SC4 imidazopyridine 4'-nitrogen and β2-Asp111, which provide a design paradigm for β2-AMPK therapeutics. The α2β2γ1/SC4 structure reveals an interaction between a β2 N-terminal α helix and the α2 autoinhibitory domain. Our results provide a structure-function guide to accelerate development of potent, but importantly tissue-specific, β2-AMPK therapeutics.
Conductive textile yarns were prepared by a continuous vapor polymerization method; the application of polypyrrole by the continuous vapor polymerisation method used is designed for the easy adaptation into industrial procedures. The resultant conductive yarns were examined by longitudinal and cross-sectional views, clearly showing the varying level of penetration of the polymer into the yarns structure. It was found that for wool the optimum specific resistance was achieved by using the 400 TPM yarn with a FeCl 3 solution concentration of 80 g/L FeCl 3 to produce 1.69 Ω g/cm 2. For cotton yarn, the optimum specific resistance of 1.53 Ω g/cm 2 was obtained with 80 g/L of a FeCl 3 solution.
Soluble conducting alkyl polypyrrole polymers have been applied by either chemical polymerization of the 3-alkyl monomers or direct application of polymer emulsion to the surface. Solution, vapor and spray polymerization methods of coating poly(3-alkylpyrroles) to the surface of woven wool fabrics are explored. Conductive textile samples have also been prepared by applying emulsions of soluble prepolymerized 3-alkylpyrrole to the fabric surface. Direct applications of a conductive paint to the textile surface eliminate the exposure of the substrate to damaging oxidizing agents which allow the coating of more sensitive and delicate substrates. All textiles produced are tested for abrasion resistance and conductivity. For alkyl polypyrrole coated fabrics, the optimum carbon chain lengths are between n=10 and n=14, which result in optimum values of conductivity and solubility. The darkness of the tone is inversely related to the surface resistivity of the resulting conductive fabric. Therefore, deep black coatings have low resistivity whereas light gray coatings on a white fabric surface have higher surface resistivity. Longer alkyl chains result in higher surface resistivity in fabrics. The conductive coating of poly(3-decanylpyrrole) on the textile surface has a better abrasion resistance compared to that of an unsubstituted polypyrrole coating.
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