Zinc is a mixed antagonist of homomeric ρ1 γ-aminobutyric acid-activated channels

Y. Chang, J. Amin, D. S. Weiss

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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 γ-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 ρ1 GABA-activated channels expressed in Xenopus oocytes. Zn2+ was found to be a mixed antagonist of these recombinant ρ1 GABA receptors. The antagonism was predominately competitive at low Zn2+ concentrations (≤100 μM), whereas at high Zn2+ concentrations (>100 μM) 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 Zn2+mediated antagonism in which GABA and Zn2+ bind to distinct sites on the GABA complex. The apparent mixed antagonism may arise from different K(i) 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.

Original languageEnglish (US)
Pages (from-to)595-602
Number of pages8
JournalMolecular pharmacology
Volume47
Issue number3
StatePublished - Jan 1 1995
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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