Zinc modulates antagonist interactions with D2-like dopamine receptors through distinct molecular mechanisms

John A. Schetz, Alice Chu, 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: D(2L), 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 D4 receptor is noncompetitive by both equilibrium and kinetic measures (lower B(max) and essentially no change in k(off)), whereas the corresponding inhibition of zinc at D(2L) and D3 receptors is primarily characterized by competitive allosterism (increases in K(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 D(2L) 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 D(2L) 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.

Original languageEnglish
Pages (from-to)956-964
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume289
Issue number2
StatePublished - May 1999

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