Dopamine heteroreceptor complexes as therapeutic targets in Parkinson’s disease

Abstract

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.

Receptor-Receptor Interactions in the Central Nervous System

“…These changes in the receptor protomers produce marked increases in diversity and bias of GPCR function. One emerging concept in neuropsychopharmacology is that a dysfunction of the allosteric receptor-receptor interactions contributes to disease progression in mental and neurological disorders [4][5][6][7][8][9][10]. So far their stoichiometry and topology are unknown within the heteromer formed as well as the number of adapter proteins participating, including their architecture.…”

Purinergic signaling in Parkinson's disease. Relevance for treatment

“…The demonstration that A 2A receptor agonists [64] which are in balance with the D 2 homoreceptor complexes [65,66] in the striatum [20,67,68,69]. The disruption of this balance in PD makes possible to understand the ability of A 2A receptor antagonists to increase movements without worsening dyskinesias [63]. Thus, the excitatory state of the striato-pallidal GABA neurons leading to motor inhibition in PD involves a dysbalance, with increased signaling via A 2A homoreceptor complexes and reduced signaling via D 2 homoreceptor complexes.…”

Regulation of G Protein-Coupled Receptors by Ubiquitination

“…Li et al [39] demonstrated that activation of D5R promoted ubiquitination and proteasomal degradation of AT1R, but it was unclear whether the two receptors interacted directly with each other, or if it was an indirect effect mediated by downstream signaling molecules (Figure 2, 1). Accumulating evidence suggests that GPCRs can also form functional homoand heteromers as well as higher order oligomers which exhibit different signaling properties when compared to monomers [138][139][140][141][142][143][144][145][146][147]. DOR and MOR were shown to form heteromers, and depending on the ligand used, the heteromers were recycled or directed for lysosomal degradation [63].…”