Arrestins (ARR) and G protein-coupled receptor kinases (GRK) participate in homologous desensitization of many G protein-coupled receptors including dopamine receptors. The rate and extent of desensitization is sensitive to the concentration and activity of ARRs and GRKs in the cells. In their turn, the amount and activity of ARRs and GRKs can be modulated by receptor stimulation. Loss of dopamine in Parkinson's disease (PD) causes motor deficits likely related to changes in responsiveness of striatal dopamine receptors. Dopamine replacement therapy with dopamine precursor L-DOPA, although successful at first, eventually leads to motor complications. Molecular mechanisms of motor disturbances in PD and of L-DOPA- induced side effects remain elusive. Adaptations in the signal transduction pathways mediated by dopamine receptors have been implicated an in neural plasticity induced by dopaminergic denervation and L-DOPA. One of the mechanisms by which loss of dopamine or L-DOPA treatment produce behavioral responses may involve modifications in the receptor desensitization machinery. We hypothesize that loss of adequate dopaminergic stimulation in PD and subsequent non-physiological stimulation during L-DOPA therapy lead to distinct alterations in desensitization and trafficking of dopamine receptors, possibly, due to changes in expression of ARRs and/or GRKs. Specifically, loss of dopamine in PD may reduce the concentration of ARRs/GRKs in striatal neurons, thereby leading to dopamine receptor supersensitivity.
First specific aim designed to test this hypothesis includes determination of ARR/GRK expression in the striatum of Pd patients and age-matched controls at post-mortem. In the second aim, the ARR/GRK expression will be studied in the rat model of PD following nigrostriatal lesion and L-DOPA treatment.
The third aim focuses on feasibility of a novel way to modulate behavioral and molecular consequences of the nigrostriatal lesion and L-DOPA treatment by facilitating or inhibiting receptor desensitization and trafficking. To that end, lentivirus-mediated gene transfer of GRK2 or its inhibitor into the lesioned rat striatum will be used. The data generated by these studies may open a new promising venue of investigation eventually leading to novel strategies for management of PD. Drugs targeting the receptor desensitization machinery may prove particularly useful for prevention or alleviating of L-DOPA-induced motor complications.
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