Evidence against dopamine D1/D2 receptor heteromers

Area of Science:

• Neuropharmacology
• Molecular neuroscience
• G-protein-coupled receptor (GPCR) research

Background:

• Hetero-oligomerization of GPCRs offers potential for novel, selective drug development.
• Dopamine D1 and D2 receptor heteromers are hypothesized to couple to Gαq proteins, mediating specific signaling pathways.
• These D1/D2 heteromers have been implicated in the pathophysiology and treatment of depression and schizophrenia.

Purpose of the Study:

• To investigate the existence and signaling properties of dopamine D1/D2 receptor heteromers.
• To determine if SKF83959 acts as a biased agonist engaging D1/D2 heteromers to activate Gαq.
• To assess the role of these heteromers in behavioral responses relevant to psychiatric conditions.

Main Methods:

• In vitro bioluminescence resonance energy transfer (BRET) to detect receptor proximity.
• Ex vivo analysis of receptor localization and proximity in mouse brain slices.
• Behavioral assays in wild-type, knockout (KO), and knock-in mice.

Main Results:

• No evidence of Gαq or Gα11 protein coupling to D1 or D2 receptor homomers or heteromers was detected.
• SKF83959-induced behaviors were abolished in D1 receptor KO mice but intact in D2 receptor and Gαq KO mice.
• D1 and D2 receptor proteins were found to be segregated and not forming complexes in neurons, even where both promoters are active.

Conclusions:

• The data do not support SKF83959 signaling through Gαq or a D1/D2 heteromeric complex.
• The findings challenge the existence of functional D1/D2 heteromers in adult animals studied.
• This challenges the proposed therapeutic targets for depression and schizophrenia involving these specific heteromers.