CHEMOATTRACTANT RECEPTOR-SPECIFIC DIFFERENCES IN G-PROTEIN ACTIVATION RATES REGULATE EFFECTOR ENZYME AND FUNCTIONAL-RESPONSES

The hypothesis that disparate neutrophil functional responses to various chemoattractants are regulated by receptor-specific rates of G protein activation was examined in HL-60 granulocytes. The initial rates of G protein activation and the affinity of receptor-stimulated G proteins for GTP gamma S in HL-60 membranes stimulated by fMet-Leu-Phe, C5a, and leukotriene B-4 (LTB(4)) differed significantly among the chemoattractants, with a rank order of fMet-Leu-Phe > C5a > LTB(4). Equilibrium GTP gamma S binding showed that all three chemoattractants activated a common pool of G proteins. Stimulation of phospholipase D activation, measured as phosphatidylethanol generation, and superoxide release in intact cells also occurred with a rank order of fMet-Leu-Phe > C5a > LTB(4). On the other hand, the rank order of receptor affinities for ligand and of the EC(50) of chemoattractant stimulation of GTP gamma S binding was C5a > LTB(4) > fMet-Leu-Phe. C5a and LTB(4) receptor densities were similar but were less than formyl peptide receptor density. Graded pertussis toxin treatment proportionally reduced superoxide release and phospholipase D activation to all three chemoattractants. The results suggest that receptor-specific differences in G protein affinity for guanine nucleotides lead to different rates of guanine nucleotide exchange and, thereby, contribute to disparate effector enzyme and functional responses.