Coexistence of D3R typical and atypical signaling in striatonigral neurons during dopaminergic denervation. Correlation with D3nf expression changes

• Published in: Synapse (New York, N.Y.) Vol. 74; no. 8
• Main Authors: Campos Campos, Baruc, Ávalos‐Fuentes, Arturo, Piña Leyva, Celia, Sánchez‐Zavaleta, Rodolfo, Loya‐López, Santiago, Rangel‐Barajas, Claudia, Leyva‐Gómez, Gerardo, Cortés, Hernán, Erlij, David, Florán, Benjamín
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc 01.08.2020
• Subjects: Agonists; Alternative splicing; Basal ganglia; Coexistence; Cyclic AMP; D3 receptors; D3nf; Denervation; Dopamine D1 receptors; Dopamine D3 receptors; GABA release; Isoforms; mRNA; Neostriatum; Neurons; Parkinson's disease; striatonigral projections; striatum; substantia nigra reticulata; Turning behavior; γ-Aminobutyric acid
• ISSN: 0887-4476; 1098-2396
• DOI: 10.1002/syn.22152

Dopamine D3R are widely expressed in basal ganglia where interact with D1R. D3R potentiate cAMP accumulation and GABA release stimulated by D1R in striatonigral neurons through “atypical” signaling. During dopaminergic denervation, D3R signaling changes to a “typical” in which antagonizes the effects of D1R, the mechanisms of this switching are unknown. D3nf splice variant regulates membrane anchorage and function of D3R and decreases in denervation; thus, it is possible that D3R signaling switching correlates with changes in D3nf expression and increases of membranal D3R that mask D3R atypical effects. We performed experiments in unilaterally 6‐hydroxydopamine lesioned rats and found a decrease in mRNA and protein of D3nf, but not of D3R in the denervated striatum. Proximity ligation assay showed that D3R‐D3nf interaction decreased after denervation, whereas binding revealed an increased Bmax in D3R. The new D3R antagonized cAMP accumulation and GABA release stimulated by D1R; however, in the presence of N‐Ethylmaleimide (NEM), to block Gi protein signaling, activation of D3R produced its atypical signaling stimulating D1R effects. Finally, we investigated if the typical and atypical effects of D3R modulating GABA release are capable of influencing motor behavior. Injections of D3R agonist into denervated nigra decreased D1R agonist‐induced turning behavior but potentiated it in the presence of NEM. Our data indicate the coexistence of D3R typical and atypical signaling in striatonigral neurons during denervation that correlated with changes in the ratio of expression of D3nf and D3R isoforms. The coexistence of both atypical and typical signaling during denervation influences motor behavior. Dopaminergic denervation produces an increment in functional membranal D3R that opposes to D1R and D1‐D3R synergetic interactions on cAMP and GABA release. These interactions coexist during denervation, impact motor behavior and correlate with changes in D3nf isoform.