Abstract
Chemoattractant Receptor Cross-desensitization
Highlights
Mechanism of Leukocyte Activation and Regulation Chemoattractants such as the formylpeptide N-formylmethionylleucylphenylalanine,1 a complement cleavage product (C5a), leukotriene B4 (LTB4), and platelet-activating factor (PAF) were identified years ago [2]
The chemoattractants fMLP, C5a, IL-8, PAF, and LTB4 and the purinoceptor agonist ATP␥S were evaluated for their ability to crossdesensitize each other as measured by ligand-stimulated GTP␥S binding to membranes or intracellular Ca2ϩ mobilization
The ability of fMLP to induce a greater desensitization of Ca2ϩ mobilization by C5a and IL-8 was correlated with its ability to block C5a and IL-8-stimulated G-protein activation at the level of receptor/G-protein coupling
Summary
Studies suggested a complexity of receptor cross-regulation beyond the classic concepts of homologous and heterologous desensitization [12,13,14,15]. An approach to understanding “cross-desensitization” among chemoattractant receptors was provided by Didsbury et al [16] They demonstrated that in HEK293 cells transiently coexpressing receptors for fMLP and C5a, activation of one receptor resulted in cross-desensitization of Ca2ϩ mobilization stimulated by the other. The demonstration that phorbol ester caused phosphorylation of PAFR and that a PKC inhibitor blocked PAFR phosphorylation by fMLP, C5a, and IL-8 indicates that the susceptibility of PAFR to cross-desensitization is due at least in part to PKCmediated phosphorylation of PAFR This contention was extended by the finding that when a phosphorylation-deficient, truncated PAFR (mPAFR) was coexpressed in RBL-2H3 cells with either FR or CXCR1, neither fMLP nor IL-8 cross-desensitized PAF-mediated responses [26]. Arrows indicate cross-desensitization of Ca2ϩ mobilization in the absence of receptor cross-phosphorylation and G-protein uncoupling
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