Zinc is a mixed antagonist of homomeric rho 1 gamma-aminobutyric acid-activated channels.
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.
Chang
Y
Y
Department of Physiology and Biophysics, University of South Florida College of Medicine, Tampa 33612-4799.
Amin
J
J
Weiss
D S
DS
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D004347:Drug Interactions; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology*; D007473:Ion Channels / Q000187:drug effects*; D007700:Kinetics; D046911:Macromolecular Substances; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D018079:Receptors, GABA / Q000187:drug effects* / Q000378:metabolism; D012680:Sensitivity and Specificity; D014982:Xenopus laevis; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
D018756:GABA Antagonists; D007473:Ion Channels; D046911:Macromolecular Substances; D018079:Receptors, GABA; D005680:gamma-Aminobutyric Acid; D015032:Zinc