Effects of the antibiotic gentamicin on nicotinic acetylcholine receptors.
Medical treatment with the aminoglycosidic antibiotic gentamicin may produce side effects that include neuromuscular blockage and ototoxicity; which are believed to result from a dysfunction of nicotinic acetylcholine receptors (AChRs). Gentamicin is known to reversibly block ACh-currents generated by the activation of muscle-type alphabetagammadelta-AChR and neuronal alpha9-AChR. We studied the effects of gentamicin on heteromeric alphabetagammadelta-AChR and homomeric alpha7-AChR expressed in Xenopus oocytes. Prolonged treatment with gentamicin, and other antibiotics, differentially altered alphabetagammadelta- and alpha7-AChR responses. Specifically, gentamicin accelerated desensitization and did not reduce ACh-currents in oocytes expressing alphabetagammadelta-AChRs, whereas ACh-currents were reduced and desensitization was unaltered in oocytes expressing alpha7-AChRs. Moreover, acutely applied gentamicin acted as a competitive antagonist on both types of receptors and increased the rate of desensitization in alphabetagammadelta-AChR while reducing the rate of desensitization in alpha7-AChR. This data helps to better understand the action of gentamicin on muscle and nervous tissues, providing mechanistic insights that could eventually lead to improving the medical use of aminoglycosides.
Amici
Mascia
M
Laboratory of Cellular and Molecular Neurobiology, Department of Neurobiology and Behavior, University of California, Irvine, CA 92697-4550, USA. mascia.amici@uniroma1.it
Eusebi
Fabrizio
F
Miledi
Ricardo
R
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D003051:Cochlea / Q000187:drug effects; D018076:DNA, Complementary / Q000096:biosynthesis; D004594:Electrophysiology; D005839:Gentamicins / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018733:Nicotinic Antagonists; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D018075:RNA, Complementary / Q000096:biosynthesis; D011978:Receptors, Nicotinic / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D014101:Torpedo; D014722:Vestibule, Labyrinth / Q000187:drug effects; D014981:Xenopus; D064569:alpha7 Nicotinic Acetylcholine Receptor
D000900:Anti-Bacterial Agents; C579167:Chrna7 protein, human; C579166:Chrna7 protein, mouse; D018076:DNA, Complementary; D005839:Gentamicins; D018733:Nicotinic Antagonists; D018075:RNA, Complementary; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor