Dopamine heteroreceptor complexes as therapeutic targets in Parkinson’s disease

Abstract

Introduction: Several types of D2R and D1R heteroreceptor complexes were discovered in the indirect and direct pathways of the striatum, respectively. The hypothesis is given that changes in the function of the dopamine heteroreceptor complexes may help us understand the molecular mechanisms underlying the motor complications of long-term therapy in Parkinson’s disease (PD) with l-DOPA and dopamine receptor agonists.

Areas covered: In the indirect pathway, the potential role of the A2AR-D2R, A2AR-D2R-mGluR5 and D2R-NMDAR heteroreceptor complexes in PD are covered and in the direct pathway, the D1R-D3R, A1R-D1R, D1R-NMDAR and putative A1R-D1R-D3R heteroreceptor complexes.

Expert opinion: One explanation for the more powerful ability of l-DOPA treatment versus treatment with the partial dopamine receptor agonist/antagonist activity to induce dyskinesias, may be that dopamine formed from l-DOPA acts as a full agonist. The field of D1R and D2R heteroreceptor complexes in the CNS opens up a new understanding of the wearing off of the antiparkinson actions of l-DOPA and dopamine receptor agonists and the production of l-DOPA-induced dyskinesias. It can involve a reorganization of the D1R and D2R heteroreceptor complexes and a disbalance of the D1R and D2R homomers versus non-dopamine receptor homomers in the direct and indirect pathways.

Keywords:

• allosteric receptor–receptor interactions
• dimerization
• dopamine D1 receptor
• dopamine D2 receptor
• dopamine heteroreceptor complexes
• dopamine receptor agonists
• dyskinesias
• G-protein-coupled receptors
• homodimerization
• l-DOPA
• motor complications
• neurodegeneration
• Parkinson’s disease

Declaration of interest

This work has been supported by the Swedish Medical Research Council (62X-00715-50-3) and AFA Försäkring (130328) to DO Borroto-Escuela and K Fuxe. DO Borroto-Escuela belong to Academia de Biólogos Cubanos. 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.

Notes

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