Function and regulation of chemoattractant receptors

Phagocyte migration and activation at sites of inflammation is mediated thr ough chemoattractant receptors that are coupled to G-proteins. Early studie s from our laboratory demonstrated G protein-mediated phospholipase C activ ation by chemoattractants. Recently, this laboratory developed cellular and animal models to allow biochemical, cell biological and molecular genetic approaches to be used in determining the mechanisms of chemoattractant rece ptor function, regulation, and cross regulation. These studies provided evi dence that chemoattractant receptors activate distinct pathways for chemota xis and exocytosis and cross-regulate each other's function at multiple lev els. A major site of regulation is through phosphorylation of receptors by G-protein-coupled receptor kinases and by protein kinase C. In addition, th e activation of phospholipase C by chemoattractants is also regulated at ad ditional sites distal to receptor phosphorylation. These may include modula tion of G-protein activation by regulators of G-protein signaling (RGS) and modification of phospholipase C. Phosphorylation of phospholipase C beta3 by both protein kinase A and protein kinase C has been demonstrated, The fu nction and regulation of chemoattractant receptors are also being examined in mouse models. In these studies, mice deficient in leukotriene B, recepto rs have been generated by targeted gene disruption. These mice displayed re duced neutrophil accumulation in certain inflammation models and sex-relate d differences in platelet-activating-factor induced anaphylaxis.