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Differential regulation of formyl peptide and platelet-activating factor receptors: role of phospholipase Cbeta3 phosphorylation by protein kinase A

Ali, Hydar and Sozzani, Silvano and Fisher, Ian and Barr, Alastair J. and Richardson, Ricardo M. and Haribabu, Bodduluri and Snyderman, Ralph (1998) Differential regulation of formyl peptide and platelet-activating factor receptors: role of phospholipase Cbeta3 phosphorylation by protein kinase A. Journal of Biological Chemistry, 273 (18). pp. 11012-11016. ISSN 0021-9258

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Official URL: http://dx.doi.org/10.1074/jbc.273.18.11012

Abstract

Formylated peptides (e.g. n-formyl-Met-Leu-Phe (fMLP)) and platelet-activating factor (PAF) mediate chemotactic and cytotoxic responses in leukocytes through receptors coupled to G proteins that activate phospholipase C (PLC). In RBL-2H3 cells, fMLP utilizes a pertussis toxin (ptx)-sensitive G protein to activate PLC, whereas PAF utilizes a ptx-insensitive G protein. Here we demonstrate that fMLP, but not PAF, enhanced intracellular cAMP levels via a ptx-sensitive mechanism. Protein kinase A (PKA) inhibition by H-89 enhanced inositol phosphate formation stimulated by fMLP but not PAF. Furthermore, a membrane-permeable cAMP analog 8-(4-chlorophenylthio)-cAMP (cpt-cAMP) inhibited phosphoinositide hydrolysis and secretion stimulated by fMLP but not PAF. Both cpt-cAMP and fMLP stimulated PLCβ3phosphorylation in intact RBL cells. The purified catalytic subunit of PKA phosphorylated PLCβ3 immunoprecipitated from RBL cell lysate. Pretreatment of intact cells with cpt-cAMP and fMLP, but not PAF, resulted in an inhibition of subsequent PLCβ3phosphorylation by PKA in vitro. These data demonstrate that fMLP receptor, which couples to a ptx-sensitive G protein, activates both PLC and cAMP production. The resulting PKA activation phosphorylates PLCβ3 and appears to block the ability of Gβγ to activate PLC. Thus, both fMLP and PAF generate stimulatory signals for PLCβ3, but only fMLP produces a PKA-dependent inhibitory signal. This suggests a novel mechanism for the bidirectional regulation of receptors which activate PLC by ptx-sensitive G proteins.

Item Type:Article
Research Community:University of Westminster > Life Sciences, School of
ID Code:10864
Deposited On:20 Jul 2012 14:17
Last Modified:20 Jul 2012 14:17

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