Targeting the receptor-based interactome of the dopamine D1 receptor: looking for heteromer-selective drugs

ABSTRACT

Introduction: G protein-coupled receptors (GPCRs) are a superfamily of membrane proteins highly expressed in the brain that are involved in almost all functions of the CNS. During the last twenty years, a large number of GPCRs have been reported to form homodimers, heterodimers and higher order oligomers.

Areas covered: This review summarizes the functional and pharmacological characteristics of the dopamine D₁ receptor (D₁R) interactome constituted by heteromers with GPCRs or non-GPCRs. The review also focuses on heteromer-selective ligands reported for GPCRs, including those for the receptor-based interactome of D₁R.

Expert opinion: Since the D₁R plays a key role in basal ganglia motor control, where all the mentioned D₁R heteromers are present, the study of allosteric interactions within the D₁R interactome may be of high therapeutic interest for treating motor dysfunction. Moreover, several of these heteromers have also been detected in the prefrontal cortex and hippocampus, where they are involved in learning, memory and attention dysfunction. We propose that drugs targeting specific D₁R heteromers in the CNS will be more effective and safer, resulting in a reduction of side effects compared with traditional drugs targeting monomeric receptors. Heteromer-selective ligands will have a big impact on drug development with many pharmacological and clinical implications.

KEYWORDS:

• Bivalent ligand
• dopamine D₁ receptor
• G protein-coupled receptor
• interactome
• motor dysfunction
• protein-protein interaction
• receptor heteromer

Article highlights

• Many G protein-coupled receptors (GPCRs) can function as oligomeric complexes and are capable of forming receptor heteromers with novel properties due to allosteric mechanisms between protomers.

• All protein-protein interactions that can occur in a living organism is called the interactome.

• Dopamine D₁ receptor (D₁R) oligomeric complexes are involved in a lot of neurological disorders including motor dysfunctions in basal ganglia and dysfunctions in prefrontal cortex and hippocampus related with learning, memory and attention.

• To date, nine different D₁R oligomers have been reported with other receptors: the D₁R-D₁R homodimer, and the D₁R-D₃R, D₁R-D₂R, D₁R-A₁R, D₁R-H₃R, D₁R-GHSR1a, D₁R-µOR, D₁R-NMDAR, D₁R-σ₁R heteromers.

• Apart from homo and heterodimers, the receptor-based interactome of D₁R also includes heterotrimers such as D₁R-H₃R-NMDAR and D₁R-H₃R-σ₁R and heterotetramers such as D₁R-D₁R-D₃R-D₃R and D₁R-D₁R-A₁R-A₁R.

• Selective ligands displaying different affinities and efficacies for a given receptor depending on the receptor partners within the heteromer are named heteromer-selective ligands.

• The use of heteromer-selective drugs is likely to be the most promising therapeutic strategy in the near future. These drugs will have higher efficacy and lower side effects as compared with classical drugs targeting monomeric receptors.

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Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by: ‘Ministerio de Economía y Competitividad’ and European Regional Development Funds of the European Union, under Grant SAF2014-54840-R and SAF2017-87629-R; ‘Fundació La Marató de TV3’, under Grant 20140610; and ‘Generalitat de Catalunya’, under Grant 2017-SGR-1497.