Potentiation and inhibition of glycine receptors by tutin

Neuropharmacology. Feb-Mar 2011;60(2-3):453-9. doi: 10.1016/j.neuropharm.2010.10.023. Epub 2010 Oct 31.

Abstract

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 α(1) and α(2) homomeric GlyRs, with IC(50)s of 35 ± 1 and 15 ± 3 μM, respectively. The co-expression of αβ subunits reduced the potency of tutin, thus increasing the IC(50) to 51 ± 4 and 41 ± 8 μM for α(1)β and α(2)β 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 Zn(2+) 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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Picrotoxin / analogs & derivatives*
  • Picrotoxin / isolation & purification
  • Picrotoxin / metabolism
  • Picrotoxin / pharmacology
  • Plant Extracts / isolation & purification
  • Plant Extracts / metabolism
  • Plant Extracts / pharmacology*
  • Plant Leaves*
  • Protein Binding / physiology
  • Receptors, Glycine / agonists*
  • Receptors, Glycine / antagonists & inhibitors*
  • Receptors, Glycine / metabolism
  • Sesquiterpenes / isolation & purification
  • Sesquiterpenes / metabolism
  • Sesquiterpenes / pharmacology*

Substances

  • Plant Extracts
  • Receptors, Glycine
  • Sesquiterpenes
  • Picrotoxin
  • tutin