Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid
Background and Purpose The activation of α9α10 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 wo...
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2013
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00071188_v168_n4_p954_Boffi http://hdl.handle.net/20.500.12110/paper_00071188_v168_n4_p954_Boffi |
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paper:paper_00071188_v168_n4_p954_Boffi2023-06-08T14:31:37Z Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid acoustic trauma ascorbate ascorbic acid efferent olivocochlear hearing loss nicotinic receptor positive allosteric modulator redox modulation vitamin C acetylcholine alpha9alpha10 nicotinic cholinergic receptor ascorbic acid cysteine nicotinic receptor unclassified drug amino acid substitution animal cell article binding site concentration response controlled study drug mechanism evoked response nonhuman oocyte point mutation priority journal protein domain protein expression Xenopus laevis Animals Antioxidants Ascorbic Acid Dose-Response Relationship, Drug Evoked Potentials Models, Molecular Oocytes Patch-Clamp Techniques Receptors, Nicotinic Recombinant Fusion Proteins Xenopus laevis Background and Purpose The activation of α9α10 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 α9α10 nAChRs. Experimental Approach ACh-evoked responses were analysed under two-electrode voltage-clamp recordings in Xenopus laevis oocytes injected with α9 and α10 cRNAs. Key Results Ascorbic acid potentiated ACh responses in X. laevis oocytes expressing α9α10 (but not α4β2 or α7) 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 α9α10 nAChRs bearing a point mutation at the pore domain of the channel (TM2 V13T 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 α9α10 nAChRs and leads to new avenues for designing drugs with potential therapeutic use in inner ear disorders. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society. 2013 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00071188_v168_n4_p954_Boffi http://hdl.handle.net/20.500.12110/paper_00071188_v168_n4_p954_Boffi |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
acoustic trauma ascorbate ascorbic acid efferent olivocochlear hearing loss nicotinic receptor positive allosteric modulator redox modulation vitamin C acetylcholine alpha9alpha10 nicotinic cholinergic receptor ascorbic acid cysteine nicotinic receptor unclassified drug amino acid substitution animal cell article binding site concentration response controlled study drug mechanism evoked response nonhuman oocyte point mutation priority journal protein domain protein expression Xenopus laevis Animals Antioxidants Ascorbic Acid Dose-Response Relationship, Drug Evoked Potentials Models, Molecular Oocytes Patch-Clamp Techniques Receptors, Nicotinic Recombinant Fusion Proteins Xenopus laevis |
| spellingShingle |
acoustic trauma ascorbate ascorbic acid efferent olivocochlear hearing loss nicotinic receptor positive allosteric modulator redox modulation vitamin C acetylcholine alpha9alpha10 nicotinic cholinergic receptor ascorbic acid cysteine nicotinic receptor unclassified drug amino acid substitution animal cell article binding site concentration response controlled study drug mechanism evoked response nonhuman oocyte point mutation priority journal protein domain protein expression Xenopus laevis Animals Antioxidants Ascorbic Acid Dose-Response Relationship, Drug Evoked Potentials Models, Molecular Oocytes Patch-Clamp Techniques Receptors, Nicotinic Recombinant Fusion Proteins Xenopus laevis Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid |
| topic_facet |
acoustic trauma ascorbate ascorbic acid efferent olivocochlear hearing loss nicotinic receptor positive allosteric modulator redox modulation vitamin C acetylcholine alpha9alpha10 nicotinic cholinergic receptor ascorbic acid cysteine nicotinic receptor unclassified drug amino acid substitution animal cell article binding site concentration response controlled study drug mechanism evoked response nonhuman oocyte point mutation priority journal protein domain protein expression Xenopus laevis Animals Antioxidants Ascorbic Acid Dose-Response Relationship, Drug Evoked Potentials Models, Molecular Oocytes Patch-Clamp Techniques Receptors, Nicotinic Recombinant Fusion Proteins Xenopus laevis |
| description |
Background and Purpose The activation of α9α10 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 α9α10 nAChRs. Experimental Approach ACh-evoked responses were analysed under two-electrode voltage-clamp recordings in Xenopus laevis oocytes injected with α9 and α10 cRNAs. Key Results Ascorbic acid potentiated ACh responses in X. laevis oocytes expressing α9α10 (but not α4β2 or α7) 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 α9α10 nAChRs bearing a point mutation at the pore domain of the channel (TM2 V13T 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 α9α10 nAChRs and leads to new avenues for designing drugs with potential therapeutic use in inner ear disorders. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society. |
| title |
Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid |
| title_short |
Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid |
| title_full |
Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid |
| title_fullStr |
Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid |
| title_full_unstemmed |
Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid |
| title_sort |
positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid |
| publishDate |
2013 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00071188_v168_n4_p954_Boffi http://hdl.handle.net/20.500.12110/paper_00071188_v168_n4_p954_Boffi |
| _version_ |
1768546049306132480 |