Potentiation and inhibition of glycine receptors by tutin

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• 作者：Jorge Fuentealba^a ; ¹ ; ^{jorgefuentealba@udec.cl} ; Braulio Muñ ; oz^a ; ¹ ; Gonzalo Yé ; venes^b ; Gustavo Moraga-Cid^b ; Claudia Pé ; rez^c ; Leonardo Guzmá ; n^b ; Jean Michel Rigo^d ; Luis G. Aguayo^b
• 关键词：Tutin ; Glycine receptor ; Ethanol ; Zn²⁺ ; GABA_A receptor ; Picrotoxin
• 刊名：Neuropharmacology
• 出版年：2011
• 出版时间：February-March 2011
• 年：2011
• 卷：60
• 期：2-3
• 页码：453-459
• 全文大小：672 K

文摘

In the present study we characterized the effects of the South American neurotoxin tutin on recombinant glycine receptors (GlyR) expressed in HEK 293 cells using whole-cell patch-clamp techniques. Tutin induced a concentration-dependent inhibition of α₁ and α₂ homomeric GlyRs, with IC₅₀s of 35 ± 1 and 15 ± 3 μM, respectively. The co-expression of αβ subunits reduced the potency of tutin, thus increasing the IC₅₀ to 51 ± 4 and 41 ± 8 μM for α₁β and α₂β GlyRs, respectively. The inhibitory effect of tutin was competitive, independent of membrane potential and reversible suggesting a pore independent site. On the other hand, low tutin concentrations enhanced the current, which was not synergic with Zn²⁺ or ethanol. A mutation in Lys385 altered ethanol but not tutin sensitivity, suggesting different sites for modulation of α1-containing GlyRs. Our results suggest that tutin affects the GlyR by a mechanism distinct to that of picrotoxin and ethanol, and that the pharmacological profile of tutin exhibits a “Zn-like” behaviour. In conclusion, these results provide information on molecular mechanisms important for understanding the toxic effects of a recently discovered South American neurotoxin.