Journal
BRITISH JOURNAL OF PHARMACOLOGY
Volume 168, Issue 4, Pages 954-965Publisher
WILEY
DOI: 10.1111/j.1476-5381.2012.02221.x
Keywords
ascorbic acid; ascorbate; vitamin C; nicotinic receptor; positive allosteric modulator; redox modulation; efferent olivocochlear; acoustic trauma; hearing loss
Categories
Funding
- Howard Hughes Medical Institute
- Tinnitus Research Initiative
- CONICET
- UBA
- ANPCyT
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BACKGROUND AND PURPOSE The activation of alpha 9 alpha 10 nicotinic cholinergic receptors (nAChRs) present at the synapse between efferent olivocochlear fibres and cochlear hair cells can prevent acoustic trauma. Hence, pharmacological potentiators of these receptors could be useful therapeutically. In this work, we characterize ascorbic acid as a positive modulator of recombinant alpha 9 alpha 10 nAChRs. EXPERIMENTAL APPROACH ACh-evoked responses were analysed under two-electrode voltage-clamp recordings in Xenopus laevis oocytes injected with alpha 9 and alpha 10 cRNAs. KEY RESULTS Ascorbic acid potentiated ACh responses in X. laevis oocytes expressing alpha 9 alpha 10 (but not alpha 4 beta 2 or alpha 7) nAChRs, in a concentration-dependent manner, with an effective concentration range of 1-30 mM. The compound did not affect the receptor'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 alpha 9 alpha 10 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 IMPLICATIONS The present work describes one of the few agents that activates or potentiates alpha 9 alpha 10 nAChRs and leads to new avenues for designing drugs with potential therapeutic use in inner ear disorders.
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