Intensity and kinetics of the respiratory burst of human neutrophils in relation to receptor occupancy and rate of occupation by formylmethionylleucylphenylalanine.
Studies on the relationship between the binding of fMet-Leu-Phe and the respiratory response in human neutrophils have been carried out under two different conditions of stimulus presentation, i.e., instantaneously and over a period of time. The main findings are as follows (1) Under the first condition the activation of the respiratory response reaches the maximum value very quickly, when the receptor occupancy is less than 20% that at equilibrium. After reaching this maximal value, the activated respiration progressively decreases, while the specific binding of the stimulant continues until equilibrium. (2) Under the second condition, i.e., when the stimulus to neutrophils is presented over a time of 1, 2 or 4 min, the respiratory response (and also the secretory one) is depressed or absent, and the initial rate of the binding (initial Vass) is lower, but the maximal values of the receptor occupancy at equilibrium and of the rate of receptor occupation (maximal Vass) are similar and only slightly lower than those reached under the condition of instantaneous presentation of the stimulus. (3) This form of desensitization is specific for fMet-Leu-Phe and does not consist of the inactivation of the target (NADPH oxidase), since neutrophils desensitized by the slow presentation of the peptide are able to respond to a second challenge with other stimulants. These results indicate that: (1) the efficacy of the stimulus-receptor complexes is short-lived; (2) the intensity of the respiratory response is dependent on the rate of reaching a threshold of binding; (3) when this initial rate is slow, owing to the slow presentation of the stimulus, a specific desensitization takes place, indicating the existence of a molecular mechanism, linked in some way to the initial rate of binding, that modulates the capacity of the stimulus-receptor complexes to transduce signals for cell responses. The physiological role of this type of desensitization is discussed.
De Togni
P
P
Bellavite
P
P
Della Bianca
V
V
Grzeskowiak
M
M
Rossi
F
F
D000328:Adult; D003208:Concanavalin A / Q000494:pharmacology; D004361:Drug Tolerance; D006801:Humans; D007700:Kinetics; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D009504:Neutrophils / Q000378:metabolism*; D010101:Oxygen Consumption; D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D044042:Receptors, Formyl Peptide; D011971:Receptors, Immunologic; D003208:Concanavalin A; D009240:N-Formylmethionine Leucyl-Phenylalanine; D013755:Tetradecanoylphorbol Acetate