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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS045117-03
Application #
6917329
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Refolo, Lorenzo
Project Start
2003-08-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$322,763
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Gurevich, Vsevolod V; Gurevich, Eugenia V (2018) GPCRs and Signal Transducers: Interaction Stoichiometry. Trends Pharmacol Sci 39:672-684
Gurevich, Vsevolod V; Gurevich, Eugenia V (2015) Analyzing the roles of multi-functional proteins in cells: The case of arrestins and GRKs. Crit Rev Biochem Mol Biol 50:440-52
Gurevich, E V; Gurevich, V V (2015) Beyond traditional pharmacology: new tools and approaches. Br J Pharmacol 172:3229-41
Ahmed, M Rafiuddin; Bychkov, Evgeny; Kook, Seunghyi et al. (2015) Overexpression of GRK6 rescues L-DOPA-induced signaling abnormalities in the dopamine-depleted striatum of hemiparkinsonian rats. Exp Neurol 266:42-54
Kook, S; Zhan, X; Cleghorn, W M et al. (2014) Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death. Cell Death Differ 21:172-84
Song, Xiufeng; Seo, Jungwon; Baameur, Faiza et al. (2013) Rapid degeneration of rod photoreceptors expressing self-association-deficient arrestin-1 mutant. Cell Signal 25:2613-24
Gurevich, Eugenia V; Tesmer, John J G; Mushegian, Arcady et al. (2012) G protein-coupled receptor kinases: more than just kinases and not only for GPCRs. Pharmacol Ther 133:40-69
Bychkov, E R; Ahmed, M R; Gurevich, V V et al. (2011) Reduced expression of G protein-coupled receptor kinases in schizophrenia but not in schizoaffective disorder. Neurobiol Dis 44:248-58
Ahmed, M Rafiuddin; Zhan, Xuanzhi; Song, Xiufeng et al. (2011) Ubiquitin ligase parkin promotes Mdm2-arrestin interaction but inhibits arrestin ubiquitination. Biochemistry 50:3749-63
Gurevich, Vsevolod V; Hanson, Susan M; Song, Xiufeng et al. (2011) The functional cycle of visual arrestins in photoreceptor cells. Prog Retin Eye Res 30:405-30

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