Glutamate transporters are oxidant-vulnerable: a molecular link between oxidative and excitotoxic neurodegeneration?

摘要: A number of neurological cases characterized by sensory disturbances and ataxia were described in the 1950s Minamata, Japan. Such syndromes attributed to ingestion fish contaminated with methylmercury (MeHg)[71xHarada, M. Crit. Rev. Toxicol. 1995; 25: 1–24Crossref | PubMed Scopus (832)See all References[71]. Poisoning elementary mercury (Hg°) vapours was also shown produce symptoms; these often appeared at low brain levels metal (≤1 μm), that is markedly below threshold for direct inhibition cerebral metabolism function[72xAlbrecht, J Matyia, E. Metab. Brain Dis. 1996; 11: 175–184Crossref (33)See References[72]. In such instances, neurotoxicity proposed be indirect.Several lines evidence indicate a glutamate-mediated excitotoxic mechanism probably involved. Thus, NMDA receptor antagonists effectively blocked neurotoxic action neuronal cultures[73xPark, S.T, Lim, K.T, Chung, Y.T, Kim, S.U. Neurotoxicology. 17: 37–46PubMedSee References[73]. Moreover, co-application nontoxic concentrations glutamate led appearance typical lesions[74xMatyia, E Albrecht, J. Neurosci. Lett. 1993; 158: 155–158Crossref (23)See References[74]. However, other mechanisms as free-radical formation could contribute indirect toxicity[73xPark, MeHg Hg° would act, least part, via common oxidation product mercuric (Hg2+). Submicromolar Hg2+ found inhibit selectively uptake excitatory amino acids cultured astrocytes stimulate their release. This effect mimicked but not divalent cations[75xBrookes, N. Neurochem. 1988; 50: 1117–1122Crossref PubMedSee References, 76xMullaney, K.J, Vitarella, D, J, Kimelberg, H.K, Aschner, Dev. Res. 75: 261–268Crossref (15)See 77xAschner, M, Du, Y-L, Gannon, H.K. 602: 181–186Crossref (63)See References]. Most recently, micromolar potently similarly inhibited transport three distinct recombinant transporter subtypes, GLT1, GLAST EAAC1 (Ref. [8xZerangue, N Kavanaugh, M.P. Nature. 383: 634–637Crossref (521)See References[8]). reduced Vmax without affecting Km its completely reversed dithiothreitol, sulphydryl-specific reagent. Therefore, interacts functionally critical thiols conserved structures. These belong same cysteine residues involved redox modulation, since features closely resemble those hydrogen peroxide sulphydryl oxidant 5,5′-dithio-bis(2-nitrobenzoic) acid[78xTrotti, D et al. Eur. 1997; 9: 1236–1243Crossref (138)See 79xTrotti, Nussberger, S, Volterra, A, Hediger, M.A. 2207–2212Crossref