title: Polyene antibiotics increase the ionic permeability of synaptosomal plasma membranes.
abstract: The effects of antifungal heptaene antibiotics candicidin and amphotericin B were investigated in isolated cerebral cortical nerve terminals (synaptosomes). The synaptosomes were incubated with candicidin or amphotericin B in the presence or absence of external Ca2+. Candicidin (0.4-0.8 I.U./mL) increased intrasynaptosomal free Ca2+ significantly. This increase was not significantly suppressed by 30 microM verapamil or 2 microM nifedipine. In the absence of extrasynaptosomal Ca2+ intrasynaptosomal free Ca2+ was not changed by candicidin. Amphotericin B increased intrasynaptosomal free Ca2+ as well. Candicidin (0.05-0.6 I.U./mL) increased the respiration rate up to 3.5-fold above the basal rate. This response was not affected by the absence of extracellular Ca2+. Ouabain completely blocked the increase of respiration caused by candicidin, whereas tetrodotoxin was ineffective. The plasma membrane depolarized in a dose-dependent manner after candicidin (0.2-0.8 I.U./mL). The mitochondrial membrane potential was little affected and only at the highest concentrations. The results indicate that heptaene polyenes increase synaptosomal ionic permeability, which is reflected in increased Ca2(+)-influx and accelerated respiration. The increment in synaptosomal free calcium takes place probably as a nonspecific leak via typical polyene-cholesterol channels. The respiration is accelerated by increased Na(+)-permeability through the plasma membrane which stimulates the function of Na+, K(+)-ATPase and thus increases the energy demand.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, Finland.
authors.forename: O
authors.initials: O
authors.lastname: Raatikainen
authors.forename: R A
authors.initials: RA
authors.lastname: Kauppinen
authors.forename: H
authors.initials: H
authors.lastname: Komulainen
authors.forename: H
authors.initials: H
authors.lastname: Taipale
authors.forename: T
authors.initials: T
authors.lastname: Pirttilä
authors.forename: J
authors.initials: J
authors.lastname: Tuomisto
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000032:analysis; D002174:Candicidin / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D002540:Cerebral Cortex; D003600:Cytosol / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D008564:Membrane Potentials; D010101:Oxygen Consumption / Q000187:drug effects; D011090:Polyenes / Q000494:pharmacology*; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects*
chemical_list: D011090:Polyenes; D002174:Candicidin; D000666:Amphotericin B; D002118:Calcium