Coexistence of D3 R typical and atypical signaling in striatonigral neurons during dopaminergic denervation. Correlation with D3 nf expression changes

Abstract

Dopamine D₃ R are widely expressed in basal ganglia where interact with D₁ R. D₃ R potentiate cAMP accumulation and GABA release stimulated by D₁ R in striatonigral neurons through "atypical" signaling. During dopaminergic denervation, D₃ R signaling changes to a "typical" in which antagonizes the effects of D₁ R, the mechanisms of this switching are unknown. D₃ nf splice variant regulates membrane anchorage and function of D₃ R and decreases in denervation; thus, it is possible that D₃ R signaling switching correlates with changes in D₃ nf expression and increases of membranal D₃ R that mask D₃ R atypical effects. We performed experiments in unilaterally 6-hydroxydopamine lesioned rats and found a decrease in mRNA and protein of D₃ nf, but not of D₃ R in the denervated striatum. Proximity ligation assay showed that D₃ R-D₃ nf interaction decreased after denervation, whereas binding revealed an increased B_max in D₃ R. The new D₃ R antagonized cAMP accumulation and GABA release stimulated by D₁ R; however, in the presence of N-Ethylmaleimide (NEM), to block G_i protein signaling, activation of D₃ R produced its atypical signaling stimulating D₁ R effects. Finally, we investigated if the typical and atypical effects of D₃ R modulating GABA release are capable of influencing motor behavior. Injections of D₃ R agonist into denervated nigra decreased D₁ R agonist-induced turning behavior but potentiated it in the presence of NEM. Our data indicate the coexistence of D₃ R typical and atypical signaling in striatonigral neurons during denervation that correlated with changes in the ratio of expression of D₃ nf and D₃ R isoforms. The coexistence of both atypical and typical signaling during denervation influences motor behavior.

Keywords: D3 receptors; D3nf; GABA release; Parkinson's disease; striatonigral projections; striatum; substantia nigra reticulata.