Regulatory mechanisms of a chemoattractant receptor on leukocytes

Chemoattractant receptors on leukocytes initiate a number of coordinated biochemical and biological processes in a strict dose-related manner. Chemotaxis-related functions occur at low doses of chemoattractants whereas the microbicidal or secretory functions (i.e., secretion of lysosomal enzymes and superoxide anion production) require 10- to 50-fold higher concentrations. The study of the oligopeptide chemoattractant receptor on human polymorphonuclear leukocytes (PMNs) has permitted better understanding of the regulation of leukocyte function. The receptor in leukocyte membranes exists in two affinity states, which are in part interconvertible. Convertibility between a portion of the high- and low-affinity states is regulated by guanine nucleotides, which suggests that a nucleotide regulatory unit allosterically modifies receptor affinity and participates in its transduction mechanisms. Approximately one-third of the high-affinity receptors in PMN membranes are not subject to guanine nucleotide regulation. This fraction can be increased by agonist preincubation and could represent an intermediate form of the receptor before signal transduction and/or internalization. Pharmacological manipulation of viable PMNs demonstrates that the affinity and functional activity of the chemoattractant receptor can be altered in different directions by aliphatic alcohols and polyene antibiotics. The alcohols raise the receptors' affinity and enhance chemotaxis, but markedly depress chemoattractant-induced secretory mechanisms. In contrast, polyene antibiotics lower the receptors' affinity and depress chemotaxis, but enhance specific granule secretion. Thus, the chemoattractant receptors' transduction signals for chemotaxis and secretion are discrete and can be modified independently by pharmacological techniques. A relationship exists between the chemoattractant receptors' affinity and its ability to transduce signals for either chemotaxis or secretion.