Am J Physiol Cell Physiol AJP: Renal Physiology
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Am J Physiol Cell Physiol 277: C728-C738, 1999;
0363-6143/99 $5.00
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Vol. 277, Issue 4, C728-C738, October 1999

Phosphorylation-dependent stimulation of prostanoid synthesis by nigericin in cerebral endothelial cells

Helena Parfenova, John Haffner, and Charles W. Leffler

Laboratory for Research in Neonatal Physiology, Department of Physiology, University of Tennessee, Memphis, Tennessee 38163

Nigericin decreases intracellular pH (pHi) and stimulates prostanoid (PG) synthesis in endothelial cells from cerebral microvessels of newborn pigs. Nigericin-induced PG production was abolished by protein tyrosine kinase (PTK) inhibitors and amplified by phorbol 12-myristate 13-acetate (PMA) or protein tyrosine phosphatase (PTP) inhibitors. Nigericin-induced PG production in PMA-primed cells was potentiated by PTP inhibitors and abrogated by PTK inhibitors. Phospholipase A2 (PLA2) activity was stimulated by nigericin in a phosphorylation-dependent manner. Nigericin's effects on PG production and PLA2 activity were reproduced by ionomycin, which activates cytosolic PLA2 (cPLA2). cPLA2 was immunodetected in endothelial cell lysates. We found no evidence that nigericin's effects are mediated via mitogen-activated protein (MAP) kinase [extracellularly regulated kinase 1 (ERK1) and ERK2] activation: although nigericin stimulated detergent-soluble MAP kinase, its effects were not amplified by PMA or PTP inhibitors. Phosphorylation-dependent stimulation of PG synthesis was also observed when pHi was decreased by sodium propionate or a high level of CO2. Altogether, our data indicate that nigericin and decreased pHi stimulate PG synthesis by a protein phosphorylation-dependent mechanism involving cross talk between pathways mediated by PTK and PTP and by protein kinase C; cPLA2 appears to be a key enzyme affected by nigericin and decreased pHi.

prostaglandins; phospholipase A2; cyclooxygenase; vascular endothelium; protein phosphorylation


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