Coexistence of D3R typical and atypical signaling in striatonigral neurons during dopaminergic denervation. Correlation with D3nf expression changes |
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Authors: | Baruc Campos Campos Arturo Ávalos-Fuentes Celia Piña Leyva Rodolfo Sánchez-Zavaleta Santiago Loya-López Claudia Rangel-Barajas Gerardo Leyva-Gómez Hernán Cortés David Erlij Benjamín Florán |
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Institution: | 1. Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico;2. Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional, Ciudad de México, Mexico;3. Neurosciences Program, Bloomington Indiana University, Bloomington, IN, USA;4. Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, Mexico;5. Laboratorio de Medicina Genómica, Departamento de Genética, Instituto Nacional de Rehabilitación Luis Guillermo Ibarra Ibarra, Ciudad de México, Mexico;6. Department of Physiology, SUNY Downstate Medical Center, Brooklyn, NY, USA |
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Abstract: | 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. |
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Keywords: | D3 receptors D3nf GABA release Parkinson's disease striatonigral projections striatum substantia nigra reticulata |
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