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      The Anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways.

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          Abstract

          AMP-activated protein kinase (AMPK) is activated within the cell in response to multiple stresses that increase the intracellular AMP:ATP ratio. Here we show that incubation of muscle cells with the thiazolidinedione, rosiglitazone, leads to a dramatic increase in this ratio with the concomitant activation of AMPK. This finding raises the possibility that a number of the beneficial effects of the thiazolidinediones could be mediated via activation of AMPK. Furthermore, we show that in addition to the classical activation pathway, AMPK can also be stimulated without changing the levels of adenine nucleotides. In muscle cells, both hyperosmotic stress and the anti-diabetic agent, metformin, activate AMPK in the absence of any increase in the AMP:ATP ratio. However, although activation is no longer dependent on this ratio, it still involves increased phosphorylation of threonine 172 within the catalytic (alpha) subunit. AMPK stimulation in response to hyperosmotic stress does not appear to involve phosphatidylinositol 3-phosphate kinase, protein kinase C, mitogen-activated protein (MAP) kinase kinase, or p38 MAP kinase alpha or beta. Our results demonstrate that AMPK can be activated by at least two distinct signaling mechanisms and suggest that it may play a wider role in the cellular stress response than was previously understood.

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          Author and article information

          Journal
          J Biol Chem
          The Journal of biological chemistry
          American Society for Biochemistry & Molecular Biology (ASBMB)
          0021-9258
          0021-9258
          Jul 12 2002
          : 277
          : 28
          Affiliations
          [1 ] Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Hammersmith Hospital, DuCane Road, London W12 0NN, United Kingdom.
          Article
          S0021-9258(19)66477-X
          10.1074/jbc.M202489200
          11994296
          30093bb9-ade0-48ca-b75d-0e360ad6daf7

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