AGI November 40/5

Qu, Wei, Lee M. Graves, and Ronald G. Thurman. PGE2 stimulates O2 uptake in hepatic parenchymal cells: involvement of the cAMP-dependent protein kinase. Am. J. Physiol. 277 (Gastrointest. Liver Physiol. 40): G1048–G1054, 1999.—The aim of this study was to determine which PGE2 receptors and signal transduction pathways are responsible for the stimulation of oxygen uptake in liver. Hepatic parenchymal cells isolated from female Sprague-Dawley rats were incubated either with PGE2, 17-phenyl-omega-trinor PGE2 (an EP1-specific agonist), or 11-deoxy PGE1 (an EP2/EP4specific agonist), and oxygen consumption was measured. Both PGE2 and 11-deoxy PGE1 stimulated oxygen consumption. However, an EP1 agonist was without effect. Although PGE2 elevated intracellular calcium, this occurred at concentrations ,500-fold lower than that required to stimulate oxygen uptake. PGE2-stimulated increases in cAMP formation correlated well with the increase in oxygen consumption. Dibutyryl cAMP also increased oxygen consumption. Furthermore, N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide, a cell-permeable inhibitor of protein kinase A (PKA), reduced the stimulation of oxygen uptake by PGE2. Incubation of isolated parenchymal cell mitochondria with the purified catalytic subunit of PKA and ATP increased both state 3 rates of oxygen uptake and the respiratory control ratio by ,50%. Activation of these events was prevented by incubation with the PKA inhibitory peptide, PKI. These findings are consistent with the hypothesis that PGE2 stimulates oxygen consumption via an EP2 and/or EP4 subclass of receptors through the actions of cAMP on a cAMP-dependent protein kinase.