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1 Programme in Cell Biology,
2,4-Dinitrophenol (DNP) uncouples the mitochondrial oxidative
chain from ATP production, preventing oxidative metabolism. The
consequent increase in energy demand is, however, contested by cells
increasing glucose uptake to produce ATP via glycolysis. In L6 skeletal
muscle cells, DNP rapidly doubles glucose transport, reminiscent of the
effect of insulin. However, glucose transport stimulation by DNP does
not require insulin receptor substrate-1 phosphorylation and is
wortmannin insensitive. We report here that, unlike insulin, DNP does
not activate phosphatidylinositol 3-kinase, protein kinase
B/Akt, or p70 S6 kinase. However, chelation of intra- and
extracellular Ca2+ with
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic
acid-AM in conjunction with EGTA inhibited DNP-stimulated glucose
uptake by 78.9 ± 3.5%. Because
Ca2+-sensitive, conventional
protein kinase C (cPKC) can activate glucose transport in L6 muscle
cells, we examined whether cPKC may be translocated and
activated in response to DNP in L6 myotubes. Acute DNP treatment led to
translocation of cPKCs to plasma membrane. cPKC immunoprecipitated from
plasma membranes exhibited a twofold increase in kinase activity in
response to DNP. Overnight treatment with 4-phorbol 12-myristate
13-acetate downregulated cPKC isoforms 
, 
, and 
and partially
inhibited (45.0 ± 3.6%) DNP- but not insulin-stimulated
glucose uptake. Consistent with this, the PKC inhibitor
bisindolylmaleimide I blocked PKC enzyme activity at the
plasma membrane (100%) and inhibited DNP-stimulated
2-[3H]deoxyglucose
uptake (61.2 ± 2.4%) with no effect on the stimulation of glucose transport by insulin. Finally, the selective PKC- inhibitor
LY-379196 partially inhibited DNP effects on glucose uptake (66.7 ± 1.6%). The results suggest interfering with mitochondrial ATP
production acts on a signal transduction pathway independent from that
of insulin and partly mediated by
Ca2+ and cPKCs, of which PKC-
likely plays a significant role.
2,4-dinitrophenol; insulin; glucose uptake; glucose transporter-4 translocation; conventional protein kinase C
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