Block of the alpha9 nicotinic receptor by ototoxic aminoglycosides.
In the present study, we report that the alpha9 nicotinic acetylcholine receptor (nAChR) expressed in Xenopus laevis oocytes is reversibly blocked by aminoglycoside antibiotics. The aminoglycosides tested blocked the alpha9 nAChR in a concentration-dependent manner with the following rank order of potency: neomycin>gentamicin>streptomycin>amikacin>kanamycin. The antagonistic effect of gentamicin was not overcome by increasing the concentration of acetylcholine (ACh), indicative of a non-competitive type of block. Blockage of ACh-evoked currents by gentamicin was found to be voltage-dependent, being more potent at hyperpolarized than at depolarized holding potentials. Furthermore, gentamicin blockage was dependent upon the extracellular Ca(2+) concentration, shown by the fact that increments in extracellular Ca(2+) significantly reduced the potency of this aminoglycoside to block the alpha9 nAChR. Possible mechanisms of blockage by the aminoglycosides are discussed. The present results suggest that the initial reversible actions of aminoglycosides at the organ of Corti, such as the elimination of the olivocochlear efferent function, are due in part to the interaction with the native alpha9-containing cholinergic receptor of the outer hair cells.
Rothlin
C V
CV
Instituto de Investigaciones en Ingeniería Genética, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Exactas y Naturales, Vuelta de Obligado 2490, Universidad de Buenos Aires, Argentina.
Katz
E
E
Verbitsky
M
M
Vetter
D E
DE
Heinemann
S F
SF
Elgoyhen
A B
AB
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D005839:Gentamicins / Q000494:pharmacology / Q000633:toxicity; D006311:Hearing Disorders / Q000139:chemically induced*; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009847:Olivary Nucleus / Q000187:drug effects; D009865:Oocytes / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014981:Xenopus
D000900:Anti-Bacterial Agents; D002614:Chelating Agents; C498541:Chrna9 protein, rat; D005839:Gentamicins; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D002118:Calcium