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

The hypothesis that disparate neutrophil functional responses to vario us chemoattractants are regulated by receptor-specific rates of G prot ein activation was examined in HL-60 granulocytes. The initial rates o f G protein activation and the affinity of receptor-stimulated G prote ins for GTP gamma S in HL-60 membranes stimulated by fMet-Leu-Phe, C5a , and leukotriene B-4 (LTB(4)) differed significantly among the chemoa ttractants, with a rank order of fMet-Leu-Phe > C5a > LTB(4). Equilibr ium GTP gamma S binding showed that all three chemoattractants activat ed a common pool of G proteins. Stimulation of phospholipase D activat ion, measured as phosphatidylethanol generation, and superoxide releas e in intact cells also occurred with a rank order of fMet-Leu-Phe > C5 a > LTB(4). On the other hand, the rank order of receptor affinities f or ligand and of the EC(50) of chemoattractant stimulation of GTP gamm a S binding was C5a > LTB(4) > fMet-Leu-Phe. C5a and LTB(4) receptor d ensities were similar but were less than formyl peptide receptor densi ty. 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 a ffinity for guanine nucleotides lead to different rates of guanine nuc leotide exchange and, thereby, contribute to disparate effector enzyme and functional responses.