Channel modulators affect PGE(2) binding to bovine aortic endothelial cells
Department of Clinical Pharmacology, Faculty of Health Sciences, Ben-Gurion University, P.O. Box. 653, Beer-Sheva 84105, Israel.Biochimica et Biophysica Acta (Impact Factor: 4.66). 04/2002; 1570(2):113-20. DOI: 10.1016/S0304-4165(02)00160-5
PGE(2), PGF(2alpha) and the thromboxane agonist U-46619 bind to bovine aortic endothelial cells and compete on the same binding site with similar affinity. In addition, binding remains unaffected by prolonged exposure to the ligand. These characteristics differ significantly from those of any known G-coupled prostaglandin receptor. Binding of PGE(2) to the cells is reduced in the presence of the cyclic nucleotides cGMP and cAMP, and is unaffected by protein kinase inhibitors. Removal of permeable cyclic nucleotides from the cell medium results in a fast and complete restoration of PGE(2) binding to the cells, suggesting that both cyclic nucleotides reduce PGE(2) binding by a reversible interaction with the prostaglandin-binding site, without the involvement of second messenger-activated protein kinases. Our data further show that binding of prostaglandins to bovine aortic endothelial cells is sensitive to heavy metals and to activators and blockers of calcium, ATP-sensitive K(+) and chloride channels. Nickel, a specific cyclic nucleotide-gated (CNG) channel activator, decreases PGE(2) binding and so do the CNG channel activators Rp-8-Br-PET-cGMPS and Sp-8-Br-PET-cGMPS. On the other hand, the calcium channel blockers pimozide, diltiazem as well as LY-83,583, a guanylate cyclase inhibitor, which were reported to block CNG channels, enhance PGE(2) binding. The sensitivity of PGE(2) binding to selective CNG channel modifying agents, as well as the rapid and reversible interaction with cyclic nucleotides, may suggest that the common low-affinity prostanoid-binding site on bovine aortic endothelial cells is associated with a molecular entity, which possess several properties of a CNG channel.
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ABSTRACT: Prostaglandins are known to transduce their signals via 7 transmembrane prostanoid receptors, which typically signal through coupling to G proteins and downstream second messenger molecules and protein kinase activation. Recently we have shown that cyclic nucleotides affect prostaglandins binding to bovine aortic endothelial cells independent of protein kinases. Here we show that incubation of bovine aortic endothelial cells with permeable analogs of cAMP or cGMP leads to a rapid and reversible reduction in PGE(2) binding to the cells. Since cyclic nucleotides are known modulators of cyclic nucleotide gated channels, we examined the effect of a specific cyclic nucleotide gated channel blocker l-cis-diltiazem on prostaglandin E(2) (PGE(2)) binding to bovine aortic endothelial cells. L-cis-diltiazem is shown to displace PGE(2) binding to bovine aortic endothelial cells in a dose dependent manner. In addition the effect of PGE(2) and l-cis-diltiazem on thapsigargin induced calcium elevation in the cells was compared. Both agents reduced in bovine aortic endothelial cells the thapsigargin induced calcium elevation by about half. PGE(2) also retarded the time course of the response to thapsigargin. Simultaneous treatment of the cells with both PGE(2) and l-cis-diltiazem did not yield an inhibitory effect beyond that observed with l-cis-diltiazem alone. Together our data point at the cyclic nucleotide gated channels as a feasible candidate for association with the PGE(2) binding site in bovine aortic endothelial cells.European Journal of Pharmacology 09/2006; 543(1-3):8-13. DOI:10.1016/j.ejphar.2006.06.018 · 2.53 Impact Factor
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ABSTRACT: The cyclic nucleotide-gated (CNG) channel is a family of nonselective cation channels that open in response to an elevated cyclic nucleotide level. Cyclic nucleotides, particularly cAMP and cGMP, govern a great diversity of cellular functions. While the pivotal roles of CNG channels in the visual and olfactory systems have been well established in the past decade, relatively few studies were performed regarding the functional roles of CNG channels in non-neuronal systems. Cyclic nucleotides and Ca2+ are key signaling molecules in cardiovascular systems. Given that CNG channels are expressed in vascular tissues, several recent studies have explored the possible functional role of CNG channels in cardiovascular systems. This article intends to summarize some recent developments regarding the expression and functional role of CNG channels in the cardiovascular system.Future Cardiology 09/2008; 4(5):505-15. DOI:10.2217/14796622.214.171.1245
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