Distinct Dopamine D₂ Receptor Antagonists Differentially Impact D₂ Receptor Oligomerization

Area of Science:

• Neuroscience
• Pharmacology
• Molecular Biology

Background:

• Dopamine D₂ receptors (D₂R) form homodimers, and increased D₂R dimerization is linked to schizophrenia.
• Modulating D₂R homodimerization could enhance understanding of its physiological and pathological roles.

Purpose of the Study:

• To investigate the influence of D₂R antagonists on D₂R homodimer formation.
• To screen D₂R antagonists for their ability to modulate D₂R dimer equilibrium.

Main Methods:

• Utilized a live-cell reporter assay employing split Nanoluciferase complementation.
• Screened six D₂R antagonists for their real-time and long-term effects on D₂L-D₂L homodimer formation.
• Performed molecular modeling to explore drug-receptor interactions.

Main Results:

• Spiperone significantly decreased D₂L-D₂L homodimer formation by 40-60% in real-time and after prolonged incubation.
• Spiperone's effect on D₂R homodimerization was specific, as it did not alter A₂a-D₂L receptor heterodimer formation.
• Clozapine, risperidone, and droperidol did not significantly affect D₂R homodimer levels.
• Molecular modeling suggested specific spiperone-induced conformational changes in Tyr199⁵·⁴⁸ and Phe390⁶·⁵² residues.

Conclusions:

• Spiperone acts as a dissociator of dopamine D₂ receptor homodimers.
• This specific action of spiperone provides a novel pharmacological tool to study D₂R dimerization.
• Findings suggest a potential mechanism for spiperone in modulating D₂R function relevant to neuropsychiatric disorders.