Dopamine D2L receptor density influences the recruitment of β-arrestin2 and Gi1 induced by antiparkinsonian drugs. (1st April 2022)

• Record Type: Journal Article
• Authors: Ferraiolo, Mattia; Atik, Hicham; Ponthot, Romane; Koener, Beryl; Hanson, Julien; Hermans, Emmanuel
• Is Part Of: Neuropharmacology. Volume 207(2022)
• Publication Date: 2022-04-01
• Subjects: Dopamine -- D2L -- G protein -- β-arrestin -- Signaling bias -- Functional selectivity -- Antiparkinsonian -- Receptor density -- Parkinson's disease -- Luciferase -- G protein-coupled receptor; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2022.108942
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Introduction: Brain imaging studies have highlighted that the density of dopamine D2 receptors markedly fluctuates across the stages of Parkinson's disease and in response to pharmacological treatment. Moreover, receptor density constitutes a molecular determinant for the signaling profile of D2 receptor ligands. We therefore hypothesized that variations in receptor expression could influence D2 receptor response to antiparkinsonian drugs, most notably with respect to the recruitment bias between Gi1 and β-arrestin2. Methods: The recruitment bias of dopamine, pramipexole, ropinirole, and rotigotine was examined using a nanoluciferase-based biosensor for probing the interactions of the D2L receptor with either Gi1 or β-arrestin2. The characterization of the functional selectivity of these D2 receptor agonists was performed at two distinct D2L receptor densities by taking advantage of a cell model carrying an inducible system that enables the overexpression of the D2L receptor when exposed to doxycycline. Results: A high receptor density oriented the balanced signaling profile of dopamine towards a preferential recruitment of Gi1 . It also moderated the marked Gi1 and β-arrestin2 biases of pramipexole and rotigotine, respectively. At variance, the Gi1 bias of ropinirole appeared as not being influenced by D2L receptor density. Conclusions: Taken together, these observations highlight receptor density as a key driver of the signaling transducer recruitment triggered by antiparkinsonian agents. Moreover, given the putative beneficial properties of β-arrestin2 in promoting locomotion, this study provides molecular insights that position the arrestin-biased ligand rotigotine as a putatively more beneficial D2 receptor agonist for the treatment of early and late Parkinson's disease. Graphical abstract: Image 1 Highlights: Increasing D2L receptor density reshapes antiparkinsonian agents' recruitment bias. High D2L receptor density favors a Gi1 bias for dopamine. Rotigotine and pramipexole respectively present marked arrestin and Gi1 biases. The amplitude of such biases is moderated with higher D2L receptor densities. The recruitment profile of ropinirole is not affected by receptor density.