Positive modulation of the a9a10 nicotinic cholinergic receptor by ascorbic acid.

JUAN CARLOS BOFFI; CAROLINA WEDEMEYER; MARCELA LIPOVSEK; ELEONORA KATZ; DANIEL J. CALVO; ANA BELÉN ELGOYHEN

BRITISH JOURNAL OF PHARMACOLOGY

WILEY-BLACKWELL PUBLISHING, INC

Lugar: Londres; Año: 2013 vol. 168 p. 954 - 965

0007-1188

BACKGROUND AND PURPOSEThe activation of a9a10 nicotinic cholinergic receptors (nAChRs) present at the synapse between efferent olivocochlear fibresand cochlear hair cells can prevent acoustic trauma. Hence, pharmacological potentiators of these receptors could be usefultherapeutically. In this work, we characterize ascorbic acid as a positive modulator of recombinant a9a10 nAChRs.EXPERIMENTAL APPROACHACh-evoked responses were analysed under two-electrode voltage-clamp recordings in Xenopus laevis oocytes injected witha9 and a10 cRNAs.KEY RESULTSAscorbic acid potentiated ACh responses in X. laevis oocytes expressing a9a10 (but not a4b2 or a7) nAChRs, in aconcentration-dependent manner, with an effective concentration range of 1?30 mM. The compound did not affect thereceptor?s current?voltage profile nor its apparent affinity for ACh, but it significantly enhanced the maximal evoked currents(percentage of ACh maximal response, 240 20%). This effect was specific for the L form of reduced ascorbic acid.Substitution of the extracellular cysteine residues present in loop C of the ACh binding site did not affect the potentiation.Ascorbic acid turned into a partial agonist of a9a10 nAChRs bearing a point mutation at the pore domain of the channel(TM2 V13′T mutant). A positive allosteric mechanism of action rather than an antioxidant effect of ascorbic acid is proposed.CONCLUSIONS AND IMPLICATIONSThe present work describes one of the few agents that activates or potentiates a9a10 nAChRs and leads to new avenues fordesigning drugs with potential therapeutic use in inner ear disorders.