Ionic zinc may function as an endogenous ligand for the haloperidol-sensitive σ2 receptor in rat brain

Mark A. Connor, Charles Chavkin*

*Corresponding author for this work

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

In the search for an endogenous a transmitter, whose existence was previously suggested by release studies, we tested the effects of releasable substances known to be present in the hippocampus, and we determined that ionic zinc may function as an endogenous ligand for the haloperidol-sensitive σ2 site. Zn2+ displaced 1,3-di(2-[5-3H]tolyl)guanidine ([3H]DTG) from two binding sites in rat brain membranes, with an IC50 for the high affinity site of 110 ± 3 μM and for the low affinity site of 20 ± 4 mw. The σ1-selective ligand (+)-[3H]pentazocine was only weakly displaced from rat brain membranes by Zn2+ (IC50 = 1.4 ± 0.05 mM). These results indicate that the Zn2+-sensitive σ binding site corresponds to the σ2 site. The interaction between Zn2+ and the σ2 site may have physiological significance, because ionic zinc is present in synaptic vesicles in the brain and may function to regulate binding at the σ2 site. To test this hypothesis, we measured the effects of metallothionein peptide 1, a specific zinc chelator, on the actions of the putative endogenous a ligand(s) released in the hippocampus by focal electrical stimulation. Release of the endogenous σ ligand(s) was measured by competition with specific radioligand binding in live hippocampal slices. High frequency, focal, electrical stimulation of the zinc-containing mossy fibers in the hilar region of the hippocampus caused a decrease in the specific binding of [3H]DTG, (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine, or (+)-[3H]pentazocine to a sites. The decrease in [3H]DTG binding was largely blocked by metallothionein peptide 1, whereas the decrease in (+)-[3H]pentazocine binding was unaffected. These results suggest that Zn2+ may act as an endogenous ligand at σ2 sites in the rat hippocampus.

Original languageEnglish
Pages (from-to)471-479
Number of pages9
JournalMolecular Pharmacology
Volume42
Issue number3
Publication statusPublished - Sep 1992
Externally publishedYes

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