Hormonal regulation of hepatic glutaminase

Squires, Stephen Arthur (1994) Hormonal regulation of hepatic glutaminase. Masters thesis, Memorial University of Newfoundland.

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Abstract

Liver glutaminase, a mitochondrial enzyme, is known to be activated by hormones such as glucagon. Diabetes mellitus is a metabolic disease which is characterized by alterations in the insulin:glucagon ratio and, therefore, represents an in vivo situation in which to study the effects of hyperglucagonemia on liver glutaminase. Glutaminase flux was found to be increased in isolated hepatocytes and in isolated mitochondria from streptozotocin-induced diabetic rats. -- An important question is how the hormonal signal is transmitted into the mitochondria. One possibility examined is whether cAMP-mediated phosphorylation of cytosolic proteins can stimulate a mitochondrial enzyme. This was examined using the cell-permeable protein phosphatase inhibitors okadaic acid and calyculin A. In the presence of 1 mM NH₄C1, an obligatory positive effector for liver glutaminase, both inhibitors increased glutaminase flux in isolated hepatocytes. This effect was stable, existing in mitochondria isolated from okadaic acid-treated hepatocytes. The protein kinase A agonist, Sp-cAMPS, was also found to stimulate glutaminase flux in isolated hepatocytes. This stimulation was inhibited by the protein kinase A antagonist, Rp-cAMPS. These results suggest that the cAMP-dependent phosphorylation of cytosolic protein(s) can affect mitochondrial glutamine metabolism. This may also give insight into the mechanisms whereby hormones, such as glucagon, stimulate mitochondrial glutamine metabolism.

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