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, Paul A. Insel

Research output: Contribution to journalArticlepeer-review

Abstract

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 β- 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 (α1-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.

Original languageEnglish (US)
Pages (from-to)10035-10038
Number of pages4
JournalJournal of Biological Chemistry
Volume274
Issue number15
DOIs
StatePublished - Apr 9 1999

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Inhibition of phospholipase A<sub>2</sub>-mediated arachidonic acid release by cyclic AMP defines a negative feedback loop for P(2Y) receptor activation in Madin-Darby canine kidney D<sub>1</sub> cells'. Together they form a unique fingerprint.

Cite this