Artículo

Boffi, J.C.; Wedemeyer, C.; Lipovsek, M.; Katz, E.; Calvo, D.J.; Elgoyhen, A.B. "Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid" (2013) British Journal of Pharmacology. 168(4):954-965
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Abstract:

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.

Registro:

Documento: Artículo
Título:Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid
Autor:Boffi, J.C.; Wedemeyer, C.; Lipovsek, M.; Katz, E.; Calvo, D.J.; Elgoyhen, A.B.
Filiación:Instituto de Investigaciones en Ingeniería, Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Universidad de Buenos Aires, Vuelta de Obligado 2490, 1428 Buenos Aires, Argentina
Departamento de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
Palabras clave: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
Año:2013
Volumen:168
Número:4
Página de inicio:954
Página de fin:965
DOI: http://dx.doi.org/10.1111/j.1476-5381.2012.02221.x
Título revista:British Journal of Pharmacology
Título revista abreviado:Br. J. Pharmacol.
ISSN:00071188
CODEN:BJPCB
CAS:acetylcholine, 51-84-3, 60-31-1, 66-23-9; ascorbic acid, 134-03-2, 15421-15-5, 50-81-7; cysteine, 4371-52-2, 52-89-1, 52-90-4; Antioxidants; Ascorbic Acid, PQ6CK8PD0R; Chrna10 protein, rat; Chrna9 protein, rat; Receptors, Nicotinic; Recombinant Fusion Proteins
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00071188_v168_n4_p954_Boffi

Referencias:

  • Alexander, S.P., Mathie, A., Peters, J.A., Guide to Receptors and Channels (GRAC), 5th edition (2011) Br J Pharmacol, 164 (SUPPL. 1), pp. S1-S324
  • Amato, A., Connolly, C.N., Moss, S.J., Smart, T.G., Modulation of neuronal and recombinant GABAA receptors by redox reagents (1999) J Physiol, 517 (PART 1), pp. 35-50
  • Arias, H.R., Positive and negative modulation of nicotinic receptors (2010) Adv Protein Chem Struct Biol, 80, pp. 153-203
  • Arias, H.R., Gu, R.X., Feuerbach, D., Guo, B.B., Ye, Y., Wei, D.Q., Novel positive allosteric modulators of the human alpha7 nicotinic acetylcholine receptor (2011) Biochemistry, 50, pp. 5263-5278
  • Ballestero, J.A., Plazas, P.V., Kracun, S., Gomez-Casati, M.E., Taranda, J., Rothlin, C.V., Effects of quinine, quinidine, and chloroquine on alpha9alpha10 nicotinic cholinergic receptors (2005) Mol Pharmacol, 68, pp. 822-829
  • Bartos, M., Corradi, J., Bouzat, C., Structural basis of activation of cys-loop receptors: The extracellular-transmembrane interface as a coupling region (2009) Mol Neurobiol, 40, pp. 236-252
  • Bateson, A.N., The benzodiazepine site of the GABAA receptor: An old target with new potential? (2004) Sleep Med, 5 (SUPPL. 1), pp. S9-S15
  • Bertrand, D., Gopalakrishnan, M., Allosteric modulation of nicotinic acetylcholine receptors (2007) Biochem Pharmacol, 74, pp. 1155-1163
  • Bertrand, D., Bertrand, S., Cassar, S., Gubbins, E., Li, J., Gopalakrishnan, M., Positive allosteric modulation of the alpha7 nicotinic acetylcholine receptor: Ligand interactions with distinct binding sites and evidence for a prominent role of the M2-M3 segment (2008) Mol Pharmacol, 74, pp. 1407-1416
  • Bigelow, J.C., Brown, D.S., Wightman, R.M., Gamma-Aminobutyric acid stimulates the release of endogenous ascorbic acid from rat striatal tissue (1984) J Neurochem, 42, pp. 412-419
  • Bouzat, C., Barrantes, F.J., Sigworth, F.J., Changes in channel properties of acetylcholine receptors during the time course of thiol chemical modifications (1991) Pflugers Arch, 418, pp. 51-61
  • Burmeister, W.P., Cottaz, S., Rollin, P., Vasella, A., Henrissat, B., High resolution X-ray crystallography shows that ascorbate is a cofactor for myrosinase and substitutes for the function of the catalytic base (2000) J Biol Chem, 275, pp. 39385-39393
  • Calero, C.I., Calvo, D.J., Redox modulation of homomeric rho1 GABA receptors (2008) J Neurochem, 105, pp. 2367-2374
  • Calero, C.I., Vickers, E., Moraga Cid, G., Von, A.L.G., Gersdorff, H., Calvo, D.J., Allosteric modulation of retinal GABA receptors by ascorbic acid (2011) J Neurosci, 31, pp. 9672-9682
  • Chu, X.P., Close, N., Saugstad, J.A., Xiong, Z.G., ASIC1a-specific modulation of acid-sensing ion channels in mouse cortical neurons by redox reagents (2006) J Neurosci, 26, pp. 5329-5339
  • Corti, A., Casini, A.F., Pompella, A., Cellular pathways for transport and efflux of ascorbate and dehydroascorbate (2010) Arch Biochem Biophys, 500, pp. 107-115
  • Dunckley, T., Wu, J., Zhao, L., Lukas, R.J., Mutational analysis of roles for extracellular cysteine residues in the assembly and function of human alpha 7-nicotinic acetylcholine receptors (2003) Biochemistry, 42, pp. 870-876
  • Dyer, D.L., Kanai, Y., Hediger, M.A., Rubin, S.A., Said, H.M., Expression of a rabbit renal ascorbic acid transporter in Xenopus laevis oocytes (1994) Am J Physiol, 267, pp. C301-C306
  • Elgoyhen, A.B., Katz, E., The efferent medial olivocochlear-hair cell synapse (2012) J Physiol Paris, 106, pp. 47-56
  • Elgoyhen, A.B., Vetter, D.E., Katz, E., Rothlin, C.V., Heinemann, S.F., Boulter, J., Alpha10: A determinant of nicotinic cholinergic receptor function in mammalian vestibular and cochlear mechanosensory hair cells (2001) Proc Natl Acad Sci U S A, 98, pp. 3501-3506
  • Elgoyhen, A.B., Katz, E., Fuchs, P.A., The nicotinic receptor of cochlear hair cells: A possible pharmacotherapeutic target? (2009) Biochem Pharmacol, 78, pp. 712-719
  • Ellison, M., Haberlandt, C., Gomez-Casati, M.E., Watkins, M., Elgoyhen, A.B., McIntosh, J.M., Alpha-RgIA: A novel conotoxin that specifically and potently blocks the alpha9alpha10 nAChR (2006) Biochemistry, 45, pp. 1511-1517
  • Evans, R.M., Currie, L., Campbell, A., The distribution of ascorbic acid between various cellular components of blood, in normal individuals, and its relation to the plasma concentration (1982) Br J Nutr, 47, pp. 473-482
  • Gill, J.K., Savolainen, M., Young, G.T., Zwart, R., Sher, E., Millar, N.S., Agonist activation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site (2011) Proc Natl Acad Sci U S A, 108, pp. 5867-5872
  • Grunewald, R.A., Ascorbic acid in the brain (1993) Brain Res Brain Res Rev, 18, pp. 123-133
  • Harrison, F.E., May, J.M., Vitamin C function in the brain: Vital role of the ascorbate transporter SVCT2 (2009) Free Radic Biol Med, 46, pp. 719-730
  • Hediger, M.A., New view at C (2002) Nat Med, 8, pp. 445-446
  • Heinrich, U.R., Fischer, I., Brieger, J., Rumelin, A., Schmidtmann, I., Li, H., Ascorbic acid reduces noise-induced nitric oxide production in the guinea pig ear (2008) Laryngoscope, 118, pp. 837-842
  • Iorga, B., Herlem, D., Barre, E., Guillou, C., Acetylcholine nicotinic receptors: Finding the putative binding site of allosteric modulators using the 'blind docking' approach (2006) J Mol Model, 12, pp. 366-372
  • Johnson, D.S., Martinez, J., Elgoyhen, A.B., Heinemann, S.F., McIntosh, J.M., Alpha-Conotoxin ImI exhibits subtype-specific nicotinic acetylcholine receptor blockade: Preferential inhibition of homomeric alpha 7 and alpha 9 receptors (1995) Mol Pharmacol, 48, pp. 194-199
  • Klomsiri, C., Karplus, P.A., Poole, L.B., Cysteine-based redox switches in enzymes (2011) Antioxid Redox Signal, 14, pp. 1065-1077
  • Labarca, C., Nowak, M.W., Zhang, H., Tang, L., Deshpande, P., Lester, H.A., Channel gating governed symmetrically by conserved leucine residues in the M2 domain of nicotinic receptors (1995) Nature, 376, pp. 514-516
  • Landino, L.M., Koumas, M.T., Mason, C.E., Alston, J.A., Ascorbic acid reduction of microtubule protein disulfides and its relevance to protein S-nitrosylation assays (2006) Biochem Biophys Res Commun, 340, pp. 347-352
  • Le Prell, C.G., Hughes, L.F., Miller, J.M., Free radical scavengers vitamins A, C, and e plus magnesium reduce noise trauma (2007) Free Radic Biol Med, 42, pp. 1454-1463
  • Leprince, P., Chemical modification of the nicotinic cholinergic receptor of PC-12 nerve cell (1983) Biochemistry, 22, pp. 5551-5556
  • Lioudyno, M.I., Verbitsky, M., Glowatzki, E., Holt, J.C., Boulter, J., Zadina, J.E., The alpha9/alpha10-containing nicotinic ACh receptor is directly modulated by opioid peptides, endomorphin-1, and dynorphin B, proposed efferent cotransmitters in the inner ear (2002) Mol Cell Neurosci, 20, pp. 695-711
  • Lynch, E.D., Kil, J., Compounds for the prevention and treatment of noise-induced hearing loss (2005) Drug Discov Today, 10, pp. 1291-1298
  • McFadden, S.L., Woo, J.M., Michalak, N., Ding, D., Dietary vitamin C supplementation reduces noise-induced hearing loss in guinea pigs (2005) Hear Res, 202, pp. 200-208
  • McGrath, J., Drummond, G., McLachlan, E., Kilkenny, C., Wainwright, C., Guidelines for reportingexperiments involving animals: The ARRIVE guidelines (2010) Br J Pharmacol, 160, pp. 1573-1576
  • McIntosh, J.M., Plazas, P.V., Watkins, M., Gomez-Casati, M.E., Olivera, B.M., Elgoyhen, A.B., A novel alpha-conotoxin, PeIA, cloned from Conus pergrandis, discriminates between rat alpha9alpha10 and alpha7 nicotinic cholinergic receptors (2005) J Biol Chem, 280, pp. 30107-30112
  • Maison, S.F., Luebke, A.E., Liberman, M.C., Zuo, J., Efferent protection from acoustic injury is mediated via alpha9 nicotinic acetylcholine receptors on outer hair cells (2002) J Neurosci, 22, pp. 10838-10846
  • Majewska, M.D., Bell, J.A., London, E.D., Regulation of the NMDA receptor by redox phenomena: Inhibitory role of ascorbate (1990) Brain Res, 537, pp. 328-332
  • Miele, M., Fillenz, M., In vivo determination of extracellular brain ascorbate (1996) J Neurosci Methods, 70, pp. 15-19
  • Mishra, P., Prem Kumar, R., Ethayathulla, A.S., Singh, N., Sharma, S., Perbandt, M., Polysaccharide binding sites in hyaluronate lyase - Crystal structures of native phage-encoded hyaluronate lyase and its complexes with ascorbic acid and lactose (2009) FEBS J, 276, pp. 3392-3402
  • Monod, J., Wyman, J., Changeux, J.P., On the nature of allosteric transitions: A plausible model (1965) J Mol Biol, 12, pp. 88-118
  • Nelson, M.T., Joksovic, P.M., Su, P., Kang, H.W., Van Deusen, A., Baumgart, J.P., Molecular mechanisms of subtype-specific inhibition of neuronal T-type calcium channels by ascorbate (2007) J Neurosci, 27, pp. 12577-12583
  • Pan, Z.H., Zhang, X., Lipton, S.A., Redox modulation of recombinant human GABA(A) receptors (2000) Neuroscience, 98, pp. 333-338
  • Pande, J., Myer, J.P., The arginines of cytochrome c. The reduction-binding site for 2,3-butanedione and ascorbate (1980) J Biol Chem, 255, pp. 11094-11097
  • Plazas, P.V., De Rosa, M.J., Gomez-Casati, M.E., Verbitsky, M., Weisstaub, N., Katz, E., Key roles of hydrophobic rings of TM2 in gating of the alpha9alpha10 nicotinic cholinergic receptor (2005) Br J Pharmacol, 145, pp. 963-974
  • Plazas, P.V., Katz, E., Gomez-Casati, M.E., Bouzat, C., Elgoyhen, A.B., Stoichiometry of the alpha9alpha10 nicotinic cholinergic receptor (2005) J Neurosci, 25, pp. 10905-10912
  • Plazas, P.V., Savino, J., Kracun, S., Gomez-Casati, M.E., Katz, E., Parsons, C.G., Inhibition of the alpha9alpha10 nicotinic cholinergic receptor by neramexane, an open channel blocker of N-methyl-D-Aspartate receptors (2007) Eur J Pharmacol, 566, pp. 11-19
  • Portugal, C.C., Miya, V.S., Calaza Kda, C., Santos, R.A., Paes-De-Carvalho, R., Glutamate receptors modulate sodium-dependent and calcium-independent vitamin C bidirectional transport in cultured avian retinal cells (2009) J Neurochem, 108, pp. 507-520
  • Rebec, G.V., Pierce, R.C., A vitamin as neuromodulator: Ascorbate release into the extracellular fluid of the brain regulates dopaminergic and glutamatergic transmission (1994) Prog Neurobiol, 43, pp. 537-565
  • Reiber, H., Ruff, M., Uhr, M., Ascorbate concentration in human cerebrospinal fluid (CSF) and serum. Intrathecal accumulation and CSF flow rate (1993) Clin Chim Acta, 217, pp. 163-173
  • Rice, M.E., Ascorbate regulation and its neuroprotective role in the brain (2000) Trends Neurosci, 23, pp. 209-216
  • Rice, M.E., Russo-Menna, I., Differential compartmentalization of brain ascorbate and glutathione between neurons and glia (1998) Neuroscience, 82, pp. 1213-1223
  • Rose, R.C., Bode, A.M., Ocular ascorbate transport and metabolism (1991) Comp Biochem Physiol A Comp Physiol, 100, pp. 273-285
  • Rothlin, C.V., Katz, E., Verbitsky, M., Elgoyhen, A.B., The alpha9 nicotinic acetylcholine receptor shares pharmacological properties with type A gamma-Aminobutyric acid, glycine, and type 3 serotonin receptors (1999) Mol Pharmacol, 55, pp. 248-254
  • Rothlin, C.V., Katz, E., Verbitsky, M., Vetter, D.E., Heinemann, S.F., Elgoyhen, A.B., Block of the alpha9 nicotinic receptor by ototoxic aminoglycosides (2000) Neuropharmacology, 39, pp. 2525-2532
  • Rothlin, C.V., Lioudyno, M.I., Silbering, A.F., Plazas, P.V., Casati, M.E., Katz, E., Direct interaction of serotonin type 3 receptor ligands with recombinant and native alpha 9 alpha 10-containing nicotinic cholinergic receptors (2003) Mol Pharmacol, 63, pp. 1067-1074
  • Ruiz-Gomez, A., Fernandez-Shaw, C., Morato, E., Marvizon, J.C., Vazquez, J., Valdivieso, F., Sulfhydryl groups modulate the allosteric interaction between glycine binding sites at the inhibitory glycine receptor (1991) J Neurochem, 56, pp. 1690-1697
  • Ruppersberg, J.P., Stocker, M., Pongs, O., Heinemann, S.H., Frank, R., Koenen, M., Regulation of fast inactivation of cloned mammalian IK(A) channels by cysteine oxidation (1991) Nature, 352, pp. 711-714
  • Sali, A., Blundell, T.L., Comparative protein modelling by satisfaction of spatial restraints (1993) J Mol Biol, 234, pp. 779-815
  • Sharp, K.H., Mewies, M., Moody, P.C., Raven, E.L., Crystal structure of the ascorbate peroxidase-Ascorbate complex (2003) Nat Struct Biol, 10, pp. 303-307
  • Spector, R., Johanson, C., Micronutrient and urate transport in choroid plexus and kidney: Implications for drug therapy (2006) Pharm Res, 23, pp. 2515-2524
  • Stitzel, J.A., Campbell, S.M., Collins, A.C., Marks, M.J., Sulfhydryl modification of two nicotinic binding sites in mouse brain (1988) J Neurochem, 50, pp. 920-928
  • Sullivan, J.M., Traynelis, S.F., Chen, H.S., Escobar, W., Heinemann, S.F., Lipton, S.A., Identification of two cysteine residues that are required for redox modulation of the NMDA subtype of glutamate receptor (1994) Neuron, 13, pp. 929-936
  • Taranda, J., Maison, S.F., Ballestero, J.A., Katz, E., Savino, J., Vetter, D.E., A point mutation in the hair cell nicotinic cholinergic receptor prolongs cochlear inhibition and enhances noise protection (2009) PLoS Biol, 7, pp. e18
  • Thompson, A.J., Lester, H.A., Lummis, S.C., The structural basis of function in Cys-loop receptors (2010) Q Rev Biophys, 43, pp. 449-499
  • Verbitsky, M., Rothlin, C.V., Katz, E., Elgoyhen, A.B., Mixed nicotinic-muscarinic properties of the alpha9 nicotinic cholinergic receptor (2000) Neuropharmacology, 39, pp. 2515-2524
  • Vio, M.M., Holme, R.H., Hearing loss and tinnitus: 250 million people and a US10 billion potential market (2005) Drug Discov Today, 10, pp. 1263-1265
  • Young, G.T., Zwart, R., Walker, A.S., Sher, E., Millar, N.S., Potentiation of alpha7 nicotinic acetylcholine receptors via an allosteric transmembrane site (2008) Proc Natl Acad Sci U S A, 105, pp. 14686-14691
  • Zorrilla De San Martin, J., Ballestero, J., Katz, E., Elgoyhen, A.B., Fuchs, P.A., Ryanodine is a positive modulator of acetylcholine receptor gating in cochlear hair cells (2007) J Assoc Res Otolaryngol, 8, pp. 474-483

Citas:

---------- APA ----------
Boffi, J.C., Wedemeyer, C., Lipovsek, M., Katz, E., Calvo, D.J. & Elgoyhen, A.B. (2013) . Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid. British Journal of Pharmacology, 168(4), 954-965.
http://dx.doi.org/10.1111/j.1476-5381.2012.02221.x
---------- CHICAGO ----------
Boffi, J.C., Wedemeyer, C., Lipovsek, M., Katz, E., Calvo, D.J., Elgoyhen, A.B. "Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid" . British Journal of Pharmacology 168, no. 4 (2013) : 954-965.
http://dx.doi.org/10.1111/j.1476-5381.2012.02221.x
---------- MLA ----------
Boffi, J.C., Wedemeyer, C., Lipovsek, M., Katz, E., Calvo, D.J., Elgoyhen, A.B. "Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid" . British Journal of Pharmacology, vol. 168, no. 4, 2013, pp. 954-965.
http://dx.doi.org/10.1111/j.1476-5381.2012.02221.x
---------- VANCOUVER ----------
Boffi, J.C., Wedemeyer, C., Lipovsek, M., Katz, E., Calvo, D.J., Elgoyhen, A.B. Positive modulation of the α9α10 nicotinic cholinergic receptor by ascorbic acid. Br. J. Pharmacol. 2013;168(4):954-965.
http://dx.doi.org/10.1111/j.1476-5381.2012.02221.x