TY - JOUR T1 - Prostaglandin F<sub>2α</sub> Receptor-Dependent Regulation of Prostaglandin Transport JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1506 LP - 1513 DO - 10.1124/mol.59.6.1506 VL - 59 IS - 6 AU - Roberta Vezza AU - Joshua Rokach AU - Garret A. FitzGerald Y1 - 2001/06/01 UR - http://molpharm.aspetjournals.org/content/59/6/1506.abstract N2 - Prostaglandin (PG) F2α may act on its G protein-coupled receptor (FP) or be imported intracellularly via a transporter, which has high affinity for PGF2α and PGE2, but not prostacyclin (PGI2). In cells overexpressing the epitope-tagged FP together with the human prostaglandin transporter (hPGT), stimulation of the FP with PGF2α (1 nM-1 μM), or the less potent FP agonist, the isoprostane 8,12-iso-iPF2α-III, inhibited prostaglandin uptake via the hPGT. This effect was abolished by pretreatment of the cells with cholera toxin, but not with pertussis toxin. Furthermore, two dominant negative constructs directed against Gαs partially blocked FP-mediated regulation of hPGT function, also suggesting Gαs involvement in this phenomenon. Surprisingly, neither an activator (dibutyryl cyclic AMP) nor an inhibitor (H89) of cyclic AMP-dependent protein kinase had any effect on FP-mediated inhibition of hPGT activity. Furthermore, although PGF2α increases intracellular cyclic AMP via Gαs activation, it does not induce phosphorylation of the transporter, excluding a role of cyclic AMP-dependent protein kinase in hPGT regulation. Activation of the PGI2 receptor, which is also coupled to Gαs, does not regulate hPGT activity, despite markedly augmenting adenylate cyclase activation. In conclusion, activation of the FP reduces intracellular import of prostaglandins for metabolic inactivation, increasing prostanoid availability for membrane receptor activation. This effect seems to be mediated via Gαs, independent of adenylate cyclase and cyclic AMP-dependent protein kinase activation. ER -