Role of phospholipase Cbeta3 phosphorylation in the desensitization of cellular responses to platelet-activating factor.

Published

Journal Article

Platelet-activating factor (PAF) stimulates a diverse array of cellular responses through receptors coupled to G proteins that activate phospholipase C (PLC). Truncation of the cytoplasmic tail of the receptor to remove phosphorylation sites (mutant PAF receptor, mPAFR) results in enhancement of PAF-stimulated responses. Here we demonstrate that PAF or phorbol 12-myristate 13-acetate (PMA) pretreatment inhibited wild type PAFR-induced PLC-mediated responses by approximately 90%, whereas these responses to the phosphorylation-deficient mPAFR were inhibited by approximately 50%, despite normal G protein coupling, suggesting a distal inhibitory locus. PAF and PMA, as well as a membrane permeable cyclic AMP analog, stimulated phosphorylation of PLCbeta3. A protein kinase C (PKC) inhibitor blocked phosphorylation of PLCbeta3 stimulated by PAF and PMA but not by cAMP. Activation of protein kinase A (PKA) by cAMP did not result in inhibition of Ca2+ mobilization stimulated by PAF. In contrast, cAMP did inhibit the response to formylpeptide chemoattractant receptor. These data suggest that homologous desensitization of PAF-mediated responses is regulated via phosphorylation at two levels in the signaling pathway, one at the receptor and the other at PLCbeta3 mediated by PKC but not by PKA. Phosphorylation of PLCbeta3 by PKA could explain the inhibition of formylpeptide chemoattractant receptor signaling by cAMP. As PAF and formylpeptide chemoattractant receptors activate PLC via different G proteins, phosphorylation of PLCbeta3 by PKC and PKA could provide distinct regulatory control for classes of G protein-coupled receptors.

Full Text

Duke Authors

Cited Authors

  • Ali, H; Fisher, I; Haribabu, B; Richardson, RM; Snyderman, R

Published Date

  • May 1997

Published In

Volume / Issue

  • 272 / 18

Start / End Page

  • 11706 - 11709

PubMed ID

  • 9115222

Pubmed Central ID

  • 9115222

Electronic International Standard Serial Number (EISSN)

  • 1083-351X

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.272.18.11706

Language

  • eng