Zinc is a mixed antagonist of homomeric rho 1 gamma-aminobutyric acid-activated channels

Mol Pharmacol. 1995 Mar;47(3):595-602.


The transition metal Zn2+ is differentially distributed in the central nervous system, where it is proposed to be a neuromodulator. One of the documented effects of Zn2+ is the antagonism of gamma-aminobutyric acid (GABA)-mediated synaptic inhibition. This antagonism is presumed to result from a direct interaction of Zn2+ with the GABA receptor/ionophore complex, although the characteristics of Zn2+ sensitivity are dependent on the particular GABA subunit combination. In this study, we examined the effects of Zn2+ on homomeric rho 1 GABA-activated channels expressed in Xenopus oocytes. Zn2+ was found to be a mixed antagonist of these recombinant rho 1 GABA receptors. The antagonism was predominantly competitive at low Zn2+ concentrations (< or = 100 microM), whereas at high Zn2+ concentrations (> 100 microM) a noncompetitive antagonism was apparent. Evidence is presented showing that the antagonism was not due to an interaction of GABA and Zn2+ in solution but, rather, resulted from interactions of these two ligands with the GABA-activated channel. A mechanism is proposed for Zn(2+)-mediated antagonism in which GABA and Zn2+ bind to distinct sites on the GABA complex. The apparent mixed antagonism may arise from different Ki values for the binding of Zn2+ to non-agonist-bound or agonist-bound receptors. However, two distinct Zn2+ binding sites, one competitive and one noncompetitive, could also give rise to the dual antagonism.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding Sites
  • Binding, Competitive
  • Drug Interactions
  • Female
  • GABA Antagonists / pharmacology*
  • Ion Channels / drug effects*
  • Kinetics
  • Macromolecular Substances
  • Mutation
  • Oocytes / drug effects
  • Oocytes / physiology
  • Oocytes / ultrastructure
  • Receptors, GABA / drug effects*
  • Receptors, GABA / metabolism
  • Sensitivity and Specificity
  • Xenopus laevis
  • Zinc / metabolism
  • Zinc / pharmacology*
  • gamma-Aminobutyric Acid / metabolism
  • gamma-Aminobutyric Acid / pharmacology


  • GABA Antagonists
  • Ion Channels
  • Macromolecular Substances
  • Receptors, GABA
  • gamma-Aminobutyric Acid
  • Zinc