The regulation of pyruvate dehydrogenase activity in rat hippocampal slices: effect of dichloroacetate.

The effects of dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, on the phosphorylation of the alpha-subunit of pyruvate dehydrogenase and on the activity of pyruvate dehydrogenase (pyruvate:lipoamide oxidoreductase (decarboxylating and acceptor-acetylating), EC 1.2.4.1, PDH) were investigated in rat hippocampal slices. Incubating hippocampal slices with increasing concentrations of DCA resulted in an increase in the active portion of PDH, without changes in the total PDH activity, as well as an increase in the in vitro phosphorylation of alpha-PDH. The effect of DCA on PDH activity was very rapid, being almost maximal after 5 min. These results indicate that DCA in the hippocampal slice preparation inhibits PDH kinase and consequently stimulates PDH activity by decreasing its endogenous state of phosphorylation. Moreover the time-course of the effect of DCA suggests that the turnover rate of the phosphate group carried by alpha-PDH is very rapid and can be manipulated by altering PDH kinase activity.