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J Biol Chem, Vol. 273, Issue 18, 11012-11016, May 1, 1998

Differential Regulation of Formyl Peptide and Platelet-activating Factor Receptors
ROLE OF PHOSPHOLIPASE C₃ PHOSPHORYLATION BY PROTEIN KINASE A

Hydar Ali, Silvano Sozzani, Ian Fisher, Alastair J. Barr, Ricardo M. Richardson, Bodduluri Haribabu, and Ralph Snyderman

From the Departments of  Medicine and  Immunology, Duke University Medical Center, Durham, North Carolina 27710

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 PLC₃ phosphorylation in intact RBL cells. The purified catalytic subunit of PKA phosphorylated PLC₃ immunoprecipitated from RBL cell lysate. Pretreatment of intact cells with cpt-cAMP and fMLP, but not PAF, resulted in an inhibition of subsequent PLC₃ phosphorylation 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 PLC₃ and appears to block the ability of G to activate PLC. Thus, both fMLP and PAF generate stimulatory signals for PLC₃, 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.

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