Alpha-1A adrenergic receptor stimulation with phenylephrine promotes arachidonic acid release by activation of phospholipase D in rat-1 fibroblasts

Inhibition by protein kinase A

Ying Ruan, Hong Kan, Jean Hugues Parmentier, Soghra Fatima, Lee F. Allen, Kafait Malik

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

This study was conducted to determine the mechanism of arachidonic acid (AA) release elicited by phenylephrine (PHE) stimulation of alpha adrenergic receptor (AR), and its modulation by cyclic adenosine 3',5'-monophosphate (cAMP) in Rat-1 fibroblasts (R-1Fs) transfected with the alpha-1A, alpha-1B or alpha-1D AR. PHE increased AA release and also caused a marked accumulation of cAMP in R-1Fs expressing the alpha-1 AR subtypes, but not in those transfected with vector alone. PHE also enhanced phospholipase D (PLD), but not phospholipase A2 (PLA2) activity. The increase in PHE-induced AA release, PLD activity and cAMP accumulation differed among the various alpha AR subtypes with: alpha-1A > alpha-1B > alpha-1D AR. The effect of PHE to increase AA release was attenuated by C2-ceramide, an inhibitor of PLD; propranolol, a phosphatidate phosphohydrolase inhibitor; and RHC-80267, a diacylglycerol lipase inhibitor in R-1Fs expressing the alpha-1A AR. Forskolin, which activates adenylyl cyclase, increased cAMP accumulation and inhibited PHE-induced AA release and PLD activity in alpha-1A-AR-expressing R-1Fs. 8-(4-chlorophenyl-thio)-cAMP, a nonhydrolyzable analog of cAMP, also attenuated the rise in AA release and PLD activity elicited by PHE in these cells. In contrast, SQ 22536, an adenylyl cyclase inhibitor, and KT 5720, a protein kinase A inhibitor, increased PHE-induced AA release and PLD activity in R-1Fs expressing the alpha-1A AR. These data suggest that the alpha-1A, alpha-1B and alpha-1D ARs are coupled to PLD activation and cAMP accumulation. Moreover, PHE promotes AA release in R-1Fs expressing the alpha-1A AR through PLD activation. Furthermore, cAMP generated by alpha-1A AR stimulation acts as an inhibitory modulator of PLD activity and AA release via protein kinase A.

Original languageEnglish (US)
Pages (from-to)576-585
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume284
Issue number2
StatePublished - Jan 1 1998

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Adrenergic alpha-1 Receptors
Phospholipase D
Phenylephrine
Cyclic AMP-Dependent Protein Kinases
Arachidonic Acid
Cyclic AMP
Fibroblasts
Receptors, Adrenergic, alpha
Phosphatidate Phosphatase
Lipoprotein Lipase
Phospholipases A2
Colforsin
Protein Kinase Inhibitors
Adenylyl Cyclases
Propranolol

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

Alpha-1A adrenergic receptor stimulation with phenylephrine promotes arachidonic acid release by activation of phospholipase D in rat-1 fibroblasts : Inhibition by protein kinase A. / Ruan, Ying; Kan, Hong; Parmentier, Jean Hugues; Fatima, Soghra; Allen, Lee F.; Malik, Kafait.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 284, No. 2, 01.01.1998, p. 576-585.

Research output: Contribution to journalArticle

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