Persistent increase in olfactory type G-protein α subunit levels may underlie D1 receptor functional hypersensitivity in Parkinson disease

Abstract

Although L-dopa remains the most effective treatment of Parkinson disease, its long-term administration is hampered by the appearance of dyskinesia. Hypersensitivity of dopamine D1 receptors in the striatum has been suggested to contribute to the genesis of these delayed adverse effects. However, D1 receptor amounts are unchanged in Parkinson disease, suggesting alterations of downstream effectors. In rodents, striatal D 1 receptors activate adenylyl cyclase through olfactory type G-protein α subunit (Gαolf) and G-protein γ 7 subunit subunit (Gγ7). We found that Gαolf was enriched in human basal ganglia and was markedly diminished in the putamen of patients with Huntington disease, in relation with the degeneration of medium spiny neurons. In contrast, in the putamen of patients with Parkinson disease, Gαolf and Gγ7 levels were both significantly increased. In the rat, the degeneration of dopamine neurons augmented Gαolflevels in the striatal neurons, specifically at the plasma membrane, an effect accounting for the increase of D1 response on cAMP production in dopamine-depleted striatum. In lesioned rats, Gαolflevels were normalized by a 3 week treatment with L-dopa or a D 1 agonist but not with a D2-D3 agonist, supporting a Gαolf regulation by D1 receptor usage. In contrast, the increases of Gαolf levels in patients were not affected by the duration of L-dopa treatment but correlated with duration of disease. In conclusion, our results revealed in the parkinsonian putamen a prolonged elevation of Gαolflevels that may lead to a persistent D1 receptor hypersensitivity and contribute to the genesis of long-term complications of L-dopa.