HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Xing, M. Articles by Insel, P. A. Search for Related Content PubMed PubMed Citation Articles by Xing, M. Articles by Insel, P. A.

J Biol Chem, Vol. 274, Issue 15, 10035-10038, April 9, 1999

Inhibition of Phospholipase A₂-mediated Arachidonic Acid Release by Cyclic AMP Defines a Negative Feedback Loop for P_2Y Receptor Activation in Madin-Darby Canine Kidney D₁ Cells

Mingzhao Xing^§, Steven Post, Rennolds S. Ostrom, Michael Samardzija, and Paul A. Insel

From the  Department of Pharmacology, University of California, San Diego, La Jolla, California 92093 and the ^§ Department of Medicine, Greater Baltimore Medical Center, Baltimore, Maryland 21204

In Madin-Darby canine kidney D₁ cells extracellular nucleotides activate P_2Y receptors that couple to several signal transduction pathways, including stimulation of multiple phospholipases and adenylyl cyclase. For one class of P_2Y receptors, P_2Y2 receptors, this stimulation of adenylyl cyclase and increase in cAMP occurs via the conversion of phospholipase A₂ (PLA₂)-generated arachidonic acid (AA) to prostaglandins (e.g. PGE₂). These prostaglandins then stimulate adenylyl cyclase activity, presumably via activation of prostanoid receptors. In the current study we show that agents that increase cellular cAMP levels (including PGE₂, forskolin, and the -adrenergic agonist isoproterenol) can inhibit P_2Y receptor-promoted AA release. The protein kinase A (PKA) inhibitor H89 blocks this effect, suggesting that this feedback inhibition occurs via activation of PKA. Studies with PGE₂ indicate that inhibition of AA release is attributable to inhibition of mitogen-activated protein kinase activity and in turn of P_2Y receptor stimulated PLA₂ activity. Although cAMP/PKA-mediated inhibition occurs for P_2Y receptor-promoted AA release, we did not find such inhibition for epinephrine (₁-adrenergic) or bradykinin-mediated AA release. Taken together, these results indicate that negative feedback regulation via cAMP/PKA-mediated inhibition of mitogen-activated protein kinase occurs for some, but not all, classes of receptors that promote PLA₂ activation and AA release. We speculate that receptor-selective feedback inhibition occurs because PLA₂ activation by different receptors in Madin-Darby canine kidney D₁ cells involves the utilization of different signaling components that are differentially sensitive to increases in cAMP or, alternatively, because of compartmentation of signaling components.

---

Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

This article has been cited by other articles:

				C. Canetti, C. H. Serezani, R. G. Atrasz, E. S. White, D. M. Aronoff, and M. Peters-Golden Activation of Phosphatase and Tensin Homolog on Chromosome 10 Mediates the Inhibition of Fc{gamma}R Phagocytosis by Prostaglandin E2 in Alveolar Macrophages J. Immunol., December 15, 2007; 179(12): 8350 - 8356. [Abstract] [Full Text] [PDF]

				M. P. Abbracchio, G. Burnstock, J.-M. Boeynaems, E. A. Barnard, J. L. Boyer, C. Kennedy, G. E. Knight, M. Fumagalli, C. Gachet, K. A. Jacobson, et al. International Union of Pharmacology LVIII: Update on the P2Y G Protein-Coupled Nucleotide Receptors: From Molecular Mechanisms and Pathophysiology to Therapy Pharmacol. Rev., September 1, 2006; 58(3): 281 - 341. [Abstract] [Full Text] [PDF]

				R. Nandigama, M. Padmasekar, M. Wartenberg, and H. Sauer Feed Forward Cycle of Hypotonic Stress-induced ATP Release, Purinergic Receptor Activation, and Growth Stimulation of Prostate Cancer Cells J. Biol. Chem., March 3, 2006; 281(9): 5686 - 5693. [Abstract] [Full Text] [PDF]

				A. O. Akimova, N. Bourcier, S. Taurin, R. A Bundey, K. Grygorczyk, M. Gekle, P. A Insel, N. O Dulin, and S. N Orlov Cl-secretion in ATP-treated renal epithelial C7-MDCK cells is mediated by activation of P2Y1 receptors, phospholipase A2 and protein kinase A J. Physiol., November 1, 2005; 568(3): 789 - 801. [Abstract] [Full Text] [PDF]

				D. M. Aronoff, C. Canetti, and M. Peters-Golden Prostaglandin E2 Inhibits Alveolar Macrophage Phagocytosis through an E-Prostanoid 2 Receptor-Mediated Increase in Intracellular Cyclic AMP J. Immunol., July 1, 2004; 173(1): 559 - 565. [Abstract] [Full Text] [PDF]

				K. L. Hamilton, C. A. Syme, and D. C. Devor Molecular Localization of the Inhibitory Arachidonic Acid Binding Site to the Pore of hIK1 J. Biol. Chem., May 2, 2003; 278(19): 16690 - 16697. [Abstract] [Full Text] [PDF]

				M. Xing, H. Usadel, Y. Cohen, Y. Tokumaru, Z. Guo, W. B. Westra, B. C. Tong, G. Tallini, R. Udelsman, J. A. Califano, et al. Methylation of the Thyroid-stimulating Hormone Receptor Gene in Epithelial Thyroid Tumors: A Marker of Malignancy and a Cause of Gene Silencing Cancer Res., May 1, 2003; 63(9): 2316 - 2321. [Abstract] [Full Text] [PDF]

				L. I. Lemieux, S. S. Rahal, and C. R. J. Kennedy PGE2 reduces arachidonic acid release in murine podocytes: evidence for an autocrine feedback loop Am J Physiol Cell Physiol, February 1, 2003; 284(2): C302 - C309. [Abstract] [Full Text] [PDF]

				M. Teixeira, C. Bernard, E. Ferrary, and D. Butlen Purine and pyrimidine nucleotide-sensitive phospholipase A2 in ampulla from frog semicircular canal Am J Physiol Regulatory Integrative Comp Physiol, February 1, 2001; 280(2): R519 - R526. [Abstract] [Full Text] [PDF]

				A. C. Zambon, R. J. Hughes, J. G. Meszaros, J. J. Wu, B. Torres, L. L. Brunton, and P. A. Insel P2Y2 receptor of MDCK cells: cloning, expression, and cell-specific signaling Am J Physiol Renal Physiol, December 1, 2000; 279(6): F1045 - F1052. [Abstract] [Full Text] [PDF]

				W. Tian, Z. Zhang, and D. M. Cohen MAPK signaling and the kidney Am J Physiol Renal Physiol, October 1, 2000; 279(4): F593 - F604. [Abstract] [Full Text] [PDF]

				B. S. Cummings, J. McHowat, and R. G. Schnellmann Phospholipase A2s in Cell Injury and Death J. Pharmacol. Exp. Ther., September 1, 2000; 294(3): 793 - 799. [Abstract] [Full Text]

				T. V. HARTERT, R. T. DWORSKI, B. G. MELLEN, J. A. OATES, J. J. MURRAY, and J. R. SHELLER Prostaglandin E2 Decreases Allergen-stimulated Release of Prostaglandin D2 in Airways of Subjects with Asthma Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 637 - 640. [Abstract] [Full Text] [PDF]

				K. Horie and P. A. Insel Retrovirally Mediated Transfer of a G Protein-coupled Receptor Kinase (GRK) Dominant-negative Mutant Enhances Endogenous Calcitonin Receptor Signaling in Chinese Hamster Ovary Cells. GRK INHIBITION ENHANCES EXPRESSION OF RECEPTORS AND RECEPTOR mRNA J. Biol. Chem., September 15, 2000; 275(38): 29433 - 29440. [Abstract] [Full Text] [PDF]

				J. H. Evans, D. M. Spencer, A. Zweifach, and C. C. Leslie Intracellular Calcium Signals Regulating Cytosolic Phospholipase A2 Translocation to Internal Membranes J. Biol. Chem., August 3, 2001; 276(32): 30150 - 30160. [Abstract] [Full Text] [PDF]