Pharmacological targeting of G protein-coupled receptor heteromers. (November 2022)

• Record Type: Journal Article
• Authors: Moreno, Estefanía; Casajuana-Martin, Nil; Coyle, Michael; Campos, Baruc Campos; Galaj, Ewa; del Torrent, Claudia Llinas; Seyedian, Arta; Rea, William; Cai, Ning-Sheng; Bonifazi, Alessandro; Florán, Benjamín; Xi, Zheng-Xiong; Guitart, Xavier; Casadó, Vicent; Newman, Amy H.; Bishop, Christopher; Pardo, Leonardo; Ferré, Sergi
• Is Part Of: Pharmacological research. Volume 185(2022)
• Publication Date: 2022-11
• Subjects: AIMs abnormal involuntary movements -- AC adenylyl cyclase -- ANOVA analysis of variance -- ALO axial, limb, and orolingual -- BiFC bimolecular fluorescence complementation -- BRET bioluminescence resonance energy transfer -- D1R D2R, D3R, dopamine D1, D2 and D3 receptors -- DAPI 4′, 6-diamidino-2-phenylindole -- DOPAC 3, 4-dihydroxyphenylacetic acid -- ECD extracellular domain -- ECL2 extracellular loop 2 -- FAS forepaw adjusting steps -- GPCR G protein-coupled receptor -- HEK-293 T cells human embryonic kidney-293 T cells -- HIV TAT peptide HIV trans-activator of transcription peptide -- ISH in situ hybridization -- 6-OD-DA 6-hydroxydopamine -- LID L-DOPA-induced dyskinesia -- MD molecular dynamics -- M.A.D. median absolute deviation -- MFB medial forebrain bundle -- PKA protein kinasxe A -- Rluc Renilla luciferase -- TM transmembrane domain -- TR-FRET time-resolved fluorescence resonance energy transfer -- YFP yellow fluorescence protein; PG01037 (PubChem CID: 11477180) -- PG01042 (PubChem CID: 11443078) -- VK4–116 (PubChem CID: 130431318) -- SKF81297 (PubChem CID: 1218) -- Pramipexole (PubChem CID: 119570); G protein-coupled receptor (GPCR) heteromers -- Dopamine D1 receptor -- Dopamine D3 receptor -- Locomotor activation -- L-DOPA-induced dyskinesia -- Mouse -- Rat; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106476
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: A main rationale for the role of G protein-coupled receptor (GPCR) heteromers as targets for drug development is the putative ability of selective ligands for specific GPCRs to change their pharmacological properties upon GPCR heteromerization. The present study provides a proof of concept for this rationale by demonstrating that heteromerization of dopamine D1 and D3 receptors (D1 R and D3 R) influences the pharmacological properties of three structurally similar selective dopamine D3 R ligands, the phenylpiperazine derivatives PG01042, PG01037 and VK4–116. By using D1 R-D3 R heteromer-disrupting peptides, it could be demonstrated that the three D3 R ligands display different D1 R-D3 R heteromer-dependent pharmacological properties: PG01042, acting as G protein-biased agonist, counteracted D1 R-mediated signaling in the D1 R-D3 R heteromer; PG01037, acting as a D3 R antagonist cross-antagonized D1 R-mediated signaling in the D1 R-D3 R heteromer; and VK4–116 specifically acted as a ß-arrestin-biased agonist in the D1 R-D3 R heteromer. Molecular dynamics simulations predicted potential molecular mechanisms mediating these qualitatively different pharmacological properties of the selective D3 R ligands that are dependent on D1 R-D3 R heteromerization. The results of in vitro experiments were paralleled by qualitatively different pharmacological properties of the D3 R ligands in vivo . The results supported the involvement of D1 R-D3 R heteromers in the locomotor activation by D1 R agonists in reserpinized mice and L -DOPA-induced dyskinesia in rats, highlighting the D1 R-D3 R heteromer as a main pharmacological target for L -DOPA-induced dyskinesia in Parkinson's disease. More generally, the present study implies that when suspecting its pathogenetic role, a GPCR heteromer, and not its individual GPCR units, should be considered as main target for drug development. Graphical Abstract: ga1