Transductional mechanisms of chemoattractant receptors on leukocytes.

Phagocytic leukocytes contain receptors for chemoattractants on their cell surface. Binding of chemotactic factors to these receptors initiates a number of coordinated cellular responses in a strict dose-dependent manner. Motility-related functions such as shape change, cytoskeletal rearrangement, and chemotaxis are stimulated by relatively low doses of chemoattractants, while microbiocidal or cytotoxic functions (i.e., secretion of lysosomal enzymes or stimulation of the respiratory burst), require approximately 10- to 50-fold higher concentrations of these agents. The receptor for oligopeptide chemotactic factors on leukocytes has provided an important model for the study of stimulus-response coupling in phagocytic cells. This receptor on human polymorphonuclear leukocytes exists in two affinity states that are partially interconvertible. Guanine nucleotides regulate the convertibility between a portion of the high- and low-affinity states, thereby suggesting that a nucleotide regulatory protein allosterically modifies receptor affinity and participates in its transduction mechanisms. A fraction of the high-affinity receptors in PMN membranes is not subject to guanine nucleotide regulation and appears to be formed by prior exposure of the receptors to specific agonists. This high-affinity form of the oligopeptide chemoattractant receptor is rapidly internalized at 37 degrees C, and its formation may be dependent on aggregation or covalent modification of the receptor. The chemotaxis and microbiocidal functions of PMNs can be divergently manipulated by pharmacological agents indicating that the transduction mechanisms for these two types of processes are independently regulated. Aliphatic alcohols at doses that induce mild fluidization of PMN membranes increase the average affinity of the chemoattractant receptor and enhance chemotactic functions but markedly depress lysosomal enzyme secretion and the respiratory burst. In contrast, polyene antibiotics that bind to membrane cholesterol lower the receptor's affinity and depress chemotactic functions but enhance secretion of specific granule enzymes. In addition, transmethylation reactions mediated by S-adenosyl-methionine appear to regulate receptor affinity. When such reactions are blocked pharmacologically, the oligopeptide receptor on macrophages reverts to a lower average affinity form and is ineffective in transducing chemotactic as well as microbicidal functions.(ABSTRACT TRUNCATED AT 400 WORDS)

Duke Scholars

Author Ralph Snyderman Medicine