Eugenia V. Gurevich, Ph.D.

Associate Professor

eugenia.gurevich@vanderbilt.edu

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Faculty Appointments
Associate Professor of Pharmacology
Education
Ph.D., Neuroscience, Moscow State University, Moscow, RussiaM.S., Moscow State University, Moscow, RussiaB.S., Neuroscience, Moscow State University, Moscow, Russia
Office Address
422B PRB
Preston Research Building
2200 Pierce Avenue
Nashville, TN 37232-6600
Research Description
I am interested in the mechanisms of plastic changes of signaling via dopamine receptors (DA). DA receptors are extremely important for normal brain function and are often affected in brain disorders. DA receptors are G protein-coupled receptors. Persistent stimulation of DA receptors induces desensitization. The best-studied mechanism of homologous desensitization (desensitization only of the receptor that has been activated) involves two groups of proteins. Activated receptor is phosphorylated by specific G protein-coupled receptor kinases (GRKs). Activated and phosphorylated receptor then binds arrestin, an "uncoupling" protein that prevents further receptor-G protein interaction. The receptor-arrestin complex is internalized due to arrestins' interaction with clathrin and AP-2, the major components of coated pits. In endosomes, the complex dissociates, the receptor is dephosphorylated and recycled back to the plasma membrane. Alternatively, receptors can be also sent to lysosomes and degraded, thus leading to receptor down-regulation. These processes collectively are called intracellular trafficking and sorting of receptors.
Abnormal signaling via DA receptors is implicated in a number of psychiatric and neurological disorders such as Parkinson's disease and schizophrenia, as well as in drug abuse. Parkinson's disease is the second most common neurodegenerative disorder (after Alzheimer's disease). It is caused by degeneration of dopaminergic neurons in the substantia nigra. The lack of DA leads to disturbances in the basal ganglia circuitry and, consequently, to motor deficits. Dopamine replacement therapy with L-DOPA, the precursor of dopamine, is an effective way to correct motor abnormalities. However, long-term therapy often results in reduced response to the drug and motor complications such as dyskinesias (involuntary aimless movements). We are testing the idea that arrestins and GRKs play a role in motor deficits in Parkinson's disease and in drug-induced motor complications. Studies with animal models of Parkinson's disease suggest that dopaminergic denervations results in supersensitivity of striatal DA receptors. We are examining the role arrestins and GRKs in this phenomenon. Theoretically, if receptor desensitization is impaired or delayed, receptors would appear functionally supersensitive. The animal studies also show that motor response to L-DOPA administration changes over time: repeated treatment rapidly produces a phenomenon called sensitization. Sensitization is an increase in response to a drug upon repeated application, and, to a certain extent, seems to be analogous to dyskinesia in human patients. Our research is aimed at finding out whether and how arrestins and GRKs are involved in sensitization to L-DOPA.
Excessive stimulation of DA receptors often leads to hallucinations and delusions. Specific subtypes of DA receptors are targets of drugs called antipsychotics used to control psychotic symptoms in mental disorders such as schizophrenia. We are interested in the role DA receptor trafficking plays in the mechanisms of schizophrenia and actions of antipshychotics. We are also following up indications that arrestins and GRKs may play specific roles in neuronal development.
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Research Keywords
Role of dopamine receptor trafficking in neural pathology and development
Publications
Song X, Vishnivetskiy SA, Seo J, Chen J, Gurevich EV, Gurevich VV. Arrestin-1 expression level in rods: balancing functional performance and photoreceptor health. Neuroscience [print-electronic]. 2011 Feb 2/3/2011; 174: 37-49. PMID: 21075174, PMCID: PMC3020241, PII: S0306-4522(10)01494-6, DOI: 10.1016/j.neuroscience.2010.11.009, ISSN: 1873-7544.

Bychkov E, Ahmed MR, Gurevich EV. Sex differences in the activity of signalling pathways and expression of G-protein-coupled receptor kinases in the neonatal ventral hippocampal lesion model of schizophrenia. Int. J. Neuropsychopharmacol [print-electronic]. 2011 Feb; 14(1): 1-15. PMID: 20158934, PMCID: PMC2992801, PII: S1461145710000118, DOI: 10.1017/S1461145710000118, ISSN: 1469-5111.

Ahmed MR, Berthet A, Bychkov E, Porras G, Li Q, Bioulac BH, Carl YT, Bloch B, Kook S, Aubert I, Dovero S, Doudnikoff E, Gurevich VV, Gurevich EV, Bezard E. Lentiviral overexpression of GRK6 alleviates L-dopa-induced dyskinesia in experimental Parkinson's disease. Sci Transl Med. 2010 Apr 4/21/2010; 2(28): 28ra28. PMID: 20410529, PMCID: PMC2933751, PII: 2/28/28ra28, DOI: 10.1126/scitranslmed.3000664, ISSN: 1946-6242.

Gurevich VV, Gurevich EV. Custom-designed proteins as novel therapeutic tools? The case of arrestins. Expert Rev Mol Med. 2010; 12: e13. PMID: 20412604, PMCID: PMC2933791, PII: S1462399410001444, DOI: 10.1017/S1462399410001444, ISSN: 1462-3994.

Song X, Vishnivetskiy SA, Gross OP, Emelianoff K, Mendez A, Chen J, Gurevich EV, Burns ME, Gurevich VV. Enhanced arrestin facilitates recovery and protects rods lacking rhodopsin phosphorylation. Curr. Biol [print-electronic]. 2009 Apr 4/28/2009; 19(8): 700-5. PMID: 19361994, PMCID: PMC2768495, PII: S0960-9822(09)00891-4, DOI: 10.1016/j.cub.2009.02.065, ISSN: 1879-0445.

Gurevich VV, Gurevich EV. Rich tapestry of G protein-coupled receptor signaling and regulatory mechanisms. Mol. Pharmacol [print-electronic]. 2008 Aug; 74(2): 312-6. PMID: 18515421, PMCID: PMC2865845, PII: mol.108.049015, DOI: 10.1124/mol.108.049015, ISSN: 1521-0111.

Gurevich VV, Gurevich EV. How and why do GPCRs dimerize?. Trends Pharmacol. Sci [print-electronic]. 2008 May; 29(5): 234-40. PMID: 18384890, PMCID: PMC2652501, PII: S0165-6147(08)00069-2, DOI: 10.1016/j.tips.2008.02.004, ISSN: 0165-6147.

Ahmed MR, Gurevich VV, Dalby KN, Benovic JL, Gurevich EV. Haloperidol and clozapine differentially affect the expression of arrestins, receptor kinases, and extracellular signal-regulated kinase activation. J. Pharmacol. Exp. Ther [print-electronic]. 2008 Apr; 325(1): 276-83. PMID: 18178904, PMCID: PMC2629350, PII: jpet.107.131987, DOI: 10.1124/jpet.107.131987, ISSN: 1521-0103.

Bychkov ER, Gurevich VV, Joyce JN, Benovic JL, Gurevich EV. Arrestins and two receptor kinases are upregulated in Parkinson's disease with dementia. Neurobiol. Aging [print-electronic]. 2008 Mar; 29(3): 379-96. PMID: 17125886, PMCID: PMC2275668, PII: S0197-4580(06)00389-7, DOI: 10.1016/j.neurobiolaging.2006.10.012, ISSN: 1558-1497.

Ahmed MR, Bychkov E, Gurevich VV, Benovic JL, Gurevich EV. Altered expression and subcellular distribution of GRK subtypes in the dopamine-depleted rat basal ganglia is not normalized by l-DOPA treatment. J. Neurochem [print-electronic]. 2008 Mar; 104(6): 1622-36. PMID: 17996024, PMCID: PMC2628845, PII: JNC5104, DOI: 10.1111/j.1471-4159.2007.05104.x, ISSN: 1471-4159.

Gurevich VV, Gurevich EV. GPCR monomers and oligomers: it takes all kinds. Trends Neurosci [print-electronic]. 2008 Feb; 31(2): 74-81. PMID: 18199492, PMCID: PMC2366802, PII: S0166-2236(07)00302-5, DOI: 10.1016/j.tins.2007.11.007, ISSN: 0166-2236.

Gurevich VV, Gurevich EV, Cleghorn WM. Arrestins as multi-functional signaling adaptors. Handb Exp Pharmacol. 2008; (186): 15-37. PMID: 18491047, DOI: 10.1007/978-3-540-72843-6_2, ISSN: 0171-2004.

Song X, Gurevich EV, Gurevich VV. Cone arrestin binding to JNK3 and Mdm2: conformational preference and localization of interaction sites. J. Neurochem [print-electronic]. 2007 Nov; 103(3): 1053-62. PMID: 17680991, PMCID: PMC2430867, PII: JNC4842, DOI: 10.1111/j.1471-4159.2007.04842.x, ISSN: 0022-3042.

Bychkov E, Ahmed MR, Dalby KN, Gurevich EV. Dopamine depletion and subsequent treatment with L-DOPA, but not the long-lived dopamine agonist pergolide, enhances activity of the Akt pathway in the rat striatum. J. Neurochem. 2007 Aug; 102(3): 699-711. PMID: 17630981, PII: JNC4586, DOI: 10.1111/j.1471-4159.2007.04586.x, ISSN: 0022-3042.

Hanson SM, Gurevich EV, Vishnivetskiy SA, Ahmed MR, Song X, Gurevich VV. Each rhodopsin molecule binds its own arrestin. Proc. Natl. Acad. Sci. U.S.A [print-electronic]. 2007 Feb 2/27/2007; 104(9): 3125-8. PMID: 17360618, PMCID: PMC1805568, PII: 0610886104, DOI: 10.1073/pnas.0610886104, ISSN: 0027-8424.

Song X, Raman D, Gurevich EV, Vishnivetskiy SA, Gurevich VV. Visual and both non-visual arrestins in their "inactive" conformation bind JNK3 and Mdm2 and relocalize them from the nucleus to the cytoplasm. J. Biol. Chem [print-electronic]. 2006 Jul 7/28/2006; 281(30): 21491-9. PMID: 16737965, PMCID: PMC2430869, PII: M603659200, DOI: 10.1074/jbc.M603659200, ISSN: 0021-9258.

Gurevich VV, Gurevich EV. The structural basis of arrestin-mediated regulation of G-protein-coupled receptors. Pharmacol. Ther [print-electronic]. 2006 Jun; 110(3): 465-502. PMID: 16460808, PMCID: PMC2562282, PII: S0163-7258(05)00211-1, DOI: 10.1016/j.pharmthera.2005.09.008, ISSN: 0163-7258.

Gurevich EV, Gurevich VV. Arrestins: ubiquitous regulators of cellular signaling pathways. Genome Biol. 2006; 7(9): 236. PMID: 17020596, PMCID: PMC1794542, PII: gb-2006-7-9-236, DOI: 10.1186/gb-2006-7-9-236, ISSN: 1474-760X.

Guigoni C, Aubert I, Li Q, Gurevich VV, Benovic JL, Ferry S, Mach U, Stark H, Leriche L, HÃ¥kansson K, Bioulac BH, Gross CE, Sokoloff P, Fisone G, Gurevich EV, Bloch B, Bezard E. Pathogenesis of levodopa-induced dyskinesia: focus on D1 and D3 dopamine receptors. Parkinsonism Relat. Disord. 2005 Jun; 11 Suppl 1: S25-9. PMID: 15885624, PII: S1353-8020(05)00038-6, DOI: 10.1016/j.parkreldis.2004.11.005, ISSN: 1353-8020.

Nair KS, Hanson SM, Mendez A, Gurevich EV, Kennedy MJ, Shestopalov VI, Vishnivetskiy SA, Chen J, Hurley JB, Gurevich VV, Slepak VZ. Light-dependent redistribution of arrestin in vertebrate rods is an energy-independent process governed by protein-protein interactions. Neuron. 2005 May 5/19/2005; 46(4): 555-67. PMID: 15944125, PMCID: PMC2752952, PII: S0896-6273(05)00279-5, DOI: 10.1016/j.neuron.2005.03.023, ISSN: 0896-6273.

Bezard E, Gross CE, Qin L, Gurevich VV, Benovic JL, Gurevich EV. L-DOPA reverses the MPTP-induced elevation of the arrestin2 and GRK6 expression and enhanced ERK activation in monkey brain. Neurobiol. Dis. 2005 Mar; 18(2): 323-35. PMID: 15686961, PII: S0969-9961(04)00240-2, DOI: 10.1016/j.nbd.2004.10.005, ISSN: 0969-9961.

Gurevich EV, Benovic JL, Gurevich VV. Arrestin2 expression selectively increases during neural differentiation. J. Neurochem. 2004 Dec; 91(6): 1404-16. PMID: 15584917, PII: JNC2830, DOI: 10.1111/j.1471-4159.2004.02830.x, ISSN: 0022-3042.

Gurevich VV, Gurevich EV. The molecular acrobatics of arrestin activation. Trends Pharmacol. Sci. 2004 Feb; 25(2): 105-11. PMID: 15102497, PII: S0165-6147(03)00387-0, DOI: 10.1016/j.tips.2003.12.008, ISSN: 0165-6147.

Gurevich VV, Gurevich EV. The new face of active receptor bound arrestin attracts new partners. Structure. 2003 Sep; 11(9): 1037-42. PMID: 12962621, PII: S0969212603001849, ISSN: 0969-2126.

Pan L, Gurevich EV, Gurevich VV. The nature of the arrestin x receptor complex determines the ultimate fate of the internalized receptor. J. Biol. Chem [print-electronic]. 2003 Mar 3/28/2003; 278(13): 11623-32. PMID: 12525498, PII: M209532200, DOI: 10.1074/jbc.M209532200, ISSN: 0021-9258.

Joyce JN, Ryoo HL, Beach TB, Caviness JN, Stacy M, Gurevich EV, Reiser M, Adler CH. Loss of response to levodopa in Parkinson's disease and co-occurrence with dementia: role of D3 and not D2 receptors. Brain Res. 2002 Nov 11/15/2002; 955(1-2): 138-52. PMID: 12419530, PII: S0006899302033966, ISSN: 0006-8993.

Gurevich EV, Benovic JL, Gurevich VV. Arrestin2 and arrestin3 are differentially expressed in the rat brain during postnatal development. Neuroscience. 2002; 109(3): 421-36. PMID: 11823056, PII: S0306452201005115, ISSN: 0306-4522.

Gurevich EV, Robertson RT, Joyce JN. Thalamo-cortical afferents control transient expression of the dopamine D(3) receptor in the rat somatosensory cortex. Cereb. Cortex. 2001 Aug; 11(8): 691-701. PMID: 11459759, ISSN: 1047-3211.

Joyce JN, Ryoo H, Gurevich EV, Adler C, Beach T. Ventral striatal D(3) receptors and Parkinson's Disease. Parkinsonism Relat. Disord. 2001 Jul; 7(3): 225-30. PMID: 11331190, PII: S1353-8020(00)00060-2, ISSN: 1873-5126.

Gurevich EV, Kordower JH, Joyce JN. Ontogeny of the dopamine D2 receptor mRNA expressing cells in the human hippocampal formation and temporal neocortex. J. Chem. Neuroanat. 2000 Dec; 20(3-4): 307-25. PMID: 11207428, PII: S0891-0618(00)00108-3, ISSN: 0891-0618.

Smith WC, Gurevich EV, Dugger DR, Vishnivetskiy SA, Shelamer CL, McDowell JH, Gurevich VV. Cloning and functional characterization of salamander rod and cone arrestins. Invest. Ophthalmol. Vis. Sci. 2000 Aug; 41(9): 2445-55. PMID: 10937552, ISSN: 0146-0404.

Gurevich EV, Joyce JN. Dopamine D(3) receptor is selectively and transiently expressed in the developing whisker barrel cortex of the rat. J. Comp. Neurol. 2000 Apr 4/24/2000; 420(1): 35-51. PMID: 10745218, PII: 10.1002/(SICI)1096-9861(20000424)420:1<35::AID-CNE3>3.0.CO;2-K, ISSN: 0021-9967.

Joyce JN, Gurevich EV. D3 receptors and the actions of neuroleptics in the ventral striatopallidal system of schizophrenics. Ann. N. Y. Acad. Sci. 1999 Jun 6/29/1999; 877: 595-613. PMID: 10415673, ISSN: 0077-8923.

Gurevich EV, Himes JW, Joyce JN. Developmental regulation of expression of the D3 dopamine receptor in rat nucleus accumbens and islands of Calleja. J. Pharmacol. Exp. Ther. 1999 Apr; 289(1): 587-98. PMID: 10087054, ISSN: 0022-3565.

Gurevich EV, Joyce JN. Distribution of dopamine D3 receptor expressing neurons in the human forebrain: comparison with D2 receptor expressing neurons. Neuropsychopharmacology. 1999 Jan; 20(1): 60-80. PMID: 9885786, PII: S0893-133X(98)00066-9, DOI: 10.1016/S0893-133X(98)00066-9, ISSN: 0893-133X.

Joyce JN, Myers AJ, Gurevich E. Dopamine D2 receptor bands in normal human temporal cortex are absent in Alzheimer's disease. Brain Res. 1998 Feb 2/16/1998; 784(1-2): 7-17. PMID: 9518532, PII: S0006-8993(97)01005-6, ISSN: 0006-8993.

Gurevich EV, Kordower J, Joyce JN. Dopamine D2 receptor mRNA is expressed in maturing neurons of the human hippocampal and subicular fields. Neuroreport. 1997 Nov 11/10/1997; 8(16): 3605-10. PMID: 9427335, ISSN: 0959-4965.

Gurevich EV, Joyce JN. Alterations in the cortical serotonergic system in schizophrenia: a postmortem study. Biol. Psychiatry. 1997 Oct 10/1/1997; 42(7): 529-45. PMID: 9376449, PII: S0006-3223(97)00321-1, DOI: 10.1016/S0006-3223(97)00321-1, ISSN: 0006-3223.

Joyce JN, Goldsmith SG, Gurevich EV. Limbic circuits and monoamine receptors: dissecting the effects of antipsychotics from disease processes. J Psychiatr Res. 1997 Mar; 31(2): 197-217. PMID: 9278186, PII: S0022-3956(96)00043-X, ISSN: 0022-3956.

Gurevich EV, Bordelon Y, Shapiro RM, Arnold SE, Gur RE, Joyce JN. Mesolimbic dopamine D3 receptors and use of antipsychotics in patients with schizophrenia. A postmortem study. Arch. Gen. Psychiatry. 1997 Mar; 54(3): 225-32. PMID: 9075463, ISSN: 0003-990X.

Gurevich EV, Joyce JN. Comparison of [3H]paroxetine and [3H]cyanoimipramine for quantitative measurement of serotonin transporter sites in human brain. Neuropsychopharmacology. 1996 May; 14(5): 309-23. PMID: 8703300, PII: 0893-133X(95)00139-5, DOI: 10.1016/0893-133X(95)00139-5, ISSN: 0893-133X.

Murray AM, Ryoo HL, Gurevich E, Joyce JN. Localization of dopamine D3 receptors to mesolimbic and D2 receptors to mesostriatal regions of human forebrain. Proc. Natl. Acad. Sci. U.S.A. 1994 Nov 11/8/1994; 91(23): 11271-5. PMID: 7972046, PMCID: PMC45209, ISSN: 0027-8424.