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Research ArticleArticle

Zinc Modulates Antagonist Interactions with D2-Like Dopamine Receptors through Distinct Molecular Mechanisms

John A. Schetz, Alice Chu and David R. Sibley
Journal of Pharmacology and Experimental Therapeutics May 1999, 289 (2) 956-964;
John A. Schetz
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Alice Chu
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David R. Sibley
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Abstract

Recently, zinc has been shown to modulate antagonist drug interactions with the D1 dopamine receptor (Schetz and Sibley, 1997) and the dopamine transporter (Norregaard et al., 1998). We now demonstrate that zinc also reversibly and dose-dependently modulates the specific binding of the butyrophenone antagonist [3H]methylspiperone to all D2-like dopamine receptors: D2L, D3, and D4. The molecular mechanisms of zinc regulation of these D2-like receptor subtypes are distinct because zinc inhibition of [3H]methylspiperone binding to the D4receptor is noncompetitive by both equilibrium and kinetic measures (lower B max and essentially no change ink off), whereas the corresponding inhibition of zinc at D2L and D3 receptors is primarily characterized by competitive allosterism (increases inK D and k off). Interestingly, thermodynamic measurements reveal that the macroscopic properties of zinc binding are entropy-driven for all receptor subtypes, despite their having distinct molecular mechanisms. Zinc also reduces the binding affinity of the D2L receptor for [3H]raclopride, a structurally different antagonist of the substituted benzamide class. Sodium ions negatively modulate zinc inhibition of both sodium-insensitive [3H]methylspiperone binding and sodium-sensitive [3H]raclopride binding. In addition to its demonstrated effects on antagonist binding in membrane preparations, zinc also retards the functional effects of antagonist at the D2L receptor in intact cells. These findings suggest that synaptic zinc may be a factor influencing the effectiveness of therapies that rely on dopamine receptor antagonists.

Footnotes

  • Send reprint requests to: Dr. John A. Schetz, Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Building 10, Room 5C-108, 9000 Rockville Pike, Bethesda, MD 20892. E-mail:jacks{at}helix.nih.gov

  • ↵1 This work was supported by the National Institutes of Neurological Disorders and Stroke at the National Institutes of Health.

  • ↵2 Present address: University of Medicine and Dentistry of New Jersey, E-mail: chual{at}UMDNJ.EDU

  • Abbreviations:
    GABA
    γ-amino butyric acid
    CHO
    Chinese hamster ovary
    EBSS
    Earle’s balanced saline solution
    PNGC
    pseudo-noble-gas-configuration
    cAMP
    cyclic AMP
    • Received October 19, 1998.
    • Accepted January 12, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 289 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 289, Issue 2
1 May 1999
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Research ArticleArticle

Zinc Modulates Antagonist Interactions with D2-Like Dopamine Receptors through Distinct Molecular Mechanisms

John A. Schetz, Alice Chu and David R. Sibley
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 956-964;

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Research ArticleArticle

Zinc Modulates Antagonist Interactions with D2-Like Dopamine Receptors through Distinct Molecular Mechanisms

John A. Schetz, Alice Chu and David R. Sibley
Journal of Pharmacology and Experimental Therapeutics May 1, 1999, 289 (2) 956-964;
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