Dopaminergic regulation of olfactory type G-protein ¿ subunit expression in the striatum.

Abstract

BACKGROUND: In rodents, the olfactory type G-protein ¿ subunit (G¿olf) couples the dopamine D1 receptor (D1R) to adenylyl cyclase, triggering intracellular signaling and neuronal activation. In the striatum, G¿olf is enriched in the striosomes. Changes in G¿olf protein levels have been observed after dopamine depletion. However, the regulation of G¿olf expression by dopamine and dopamine receptors is not fully understood. METHODS: To address this, Striatal G¿olf expression pattern was studied in wild-type and genetically engineered mice lacking D1R, D2R (D2 receptor), and downstream regulatory element antagonist modulator (DREAM) protein whose dopamine levels were manipulated. Dopamine depletion was accomplished by 6-hydroxydopamine (6-OHDA) or by Pitx3 ablation, and dopamine replacement by chronic levodopa (l-dopa). The G¿olf levels were analyzed by immunohistochemistry, Western blot, and real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Our results demostrate that Dopamine depletion or inactivation of D1R abolished the striosomal pattern of G¿olf expression and increased G¿olf protein levels. Dopamine replacement in wild-type lesioned mice reestablished both the expression pattern and protein levels, but paradoxically increased G¿olf messenger RNA (mRNA). In D1R(-/-) mice, dopamine depletion decreased striatal G¿olf expression, whereas l-dopa did not restore either G¿olf levels or its expression pattern. Inactivation of D2R or changes in the cAMP/PKA signaling pathway downstream of G¿olf did not modify its expression. CONCLUSION: Our results show a homeostatic, negative regulation of G¿olf by dopamine and by D1R stimulation, which are also required for the striosomal G¿olf pattern. These results shed light on the regulation of G¿olf by dopamine signaling that could be involved in the pathophysiology of the maladaptive response to chronic l-dopa treatment in Parkinson's disease. © 2015 International Parkinson and Movement Disorder Society.