title: The influence of antibiotics on agonist occupation and functional states of the nicotinic acetylcholine receptor.
abstract: Four distinct classes of antibiotics, the aminoglycosides, tetracyclines, lincomycin-clindamycin, and peptides, were examined in intact BC3H-1 cells for their capacity to influence the relationship between agonist binding to the cholinergic receptor and the response elicited. The most potent inhibitors were the peptides of the polymyxin-colistin class, which at submicromolar concentrations noncompetitively blocked agonist-elicited Na+ permeability. These agents at equivalent concentrations also enhanced the apparent affinity of agonists for the receptor. Comparisons of agonist occupation of the receptor and agonist promotion of desensitization showed that the noncompetitive inhibition by peptide antibiotics occurred largely by augmenting the conversion of the receptor to a high-affinity, desensitized state. Rates of receptor desensitization were also substantially enhanced in the presence of these antibiotics. Thus, an analysis of receptor occupation and response suggests that the polymyxin antibiotics act as heterotropic allosteric effectors by promoting the conversion of the cholinergic receptor to its desensitized state. By contrast, the other antibiotics studied inhibited permeability at far higher concentrations. Although a noncompetitive component of inhibition could be identified with certain antibiotics such as neomycin, they did not appear to enhance agonist affinity. Thus, the various antibiotics differ substantially in their potencies and basic mechanisms of inhibition of the acetylcholine receptor.
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002217:Carbachol / Q000037:antagonists & inhibitors; D002463:Cell Membrane Permeability / Q000187:drug effects; D002981:Clindamycin / Q000494:pharmacology; D003039:Cobra Neurotoxin Proteins / Q000378:metabolism; D005839:Gentamicins / Q000494:pharmacology; D007700:Kinetics; D008034:Lincomycin / Q000494:pharmacology; D055666:Lipopeptides; D009355:Neomycin / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides; D010456:Peptides, Cyclic / Q000494:pharmacology; D011113:Polymyxins / Q000494:pharmacology; D011950:Receptors, Cholinergic / Q000187:drug effects* / Q000378:metabolism; D012964:Sodium / Q000378:metabolism; D013307:Streptomycin / Q000494:pharmacology; D013752:Tetracycline / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D003039:Cobra Neurotoxin Proteins; D005839:Gentamicins; D055666:Lipopeptides; D009842:Oligopeptides; D010455:Peptides; D010456:Peptides, Cyclic; D011113:Polymyxins; D011950:Receptors, Cholinergic; C013629:octapeptin antibiotics; D002981:Clindamycin; C025154:alpha-cobratoxin; D002217:Carbachol; D012964:Sodium; D008034:Lincomycin; D013752:Tetracycline; D009355:Neomycin; D013307:Streptomycin