Regulator of G Protein Signaling Proteins as Drug Targets. Current State and Future Possibilities.

Advances in Pharmacology

Volumn 62, Issue , 2011, Pages 315-347

  Sjögren, Benita ^a  

^a UNIVERSITY OF MICHIGAN MEDICAL SCHOOL   (United States)

Author keywords

Drug discovery; G protein coupled receptors; Posttranslational modification; RGS proteins

Indexed keywords

ALANINE; AXIN; CCG 4986; CCG 50014; CCG 63802; G PROTEIN COUPLED RECEPTOR; G PROTEIN COUPLED RECEPTOR KINASE 2; G PROTEIN COUPLED RECEPTOR KINASE 3; GLYCINE; GUANOSINE TRIPHOSPHATASE ACTIVATING PROTEIN; PROTEIN INHIBITOR; RGS PROTEIN; RHO GUANINE NUCLEOTIDE BINDING PROTEIN; SORTING NEXIN; UNCLASSIFIED DRUG;

ALPHA CHAIN; AMINO TERMINAL SEQUENCE; BOOK; BREAST CANCER; CARDIOVASCULAR DISEASE; CENTRAL NERVOUS SYSTEM DISEASE; DEPRESSION; DIABETES MELLITUS; DRUG DEPENDENCE; EPILEPSY; HEART ARRHYTHMIA; HUMAN; HYPERTENSION; NEOPLASM; NONHUMAN; PALMITOYLATION; PARKINSON DISEASE; PRIORITY JOURNAL; PROSTATE CANCER; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN PROTEIN INTERACTION; PROTEIN STABILITY; PROTEIN TARGETING; SIGNAL TRANSDUCTION; THROMBOSIS;

EID: 80052649285     PISSN: 10543589     EISSN: 15578925     Source Type: Book Series    
DOI: 10.1016/B978-0-12-385952-5.00002-6     Document Type: Chapter

References (138)

1. Adams J. The development of proteasome inhibitors as anticancer drugs. Cancer Cell 2004, 5:417-421.
2. Anderson G.R., Lujan R., Semenov A., Pravetoni M., Posokhova E.N., Song J.H., et al. Expression and localization of RGS9-2/G 5/R7BP complex in vivo is set by dynamic control of its constitutive degradation by cellular cysteine proteases. The Journal of Neuroscience 2007, 27:14117-14127.
3. Anderson G.R., Posokhova E., Martemyanov K.A. The R7 RGS protein family: Multi-subunit regulators of neuronal G protein signaling. Cell Biochemistry and Biophysics 2009, 54:33-46.
4. Anger T., Klintworth N., Stumpf C., Daniel W.G., Mende U., Garlichs C.D. RGS protein specificity towards Gq- and Gi/o-mediated ERK 1/2 and Akt activation, in vitro. Journal of Biochemistry and Molecular Biology 2007, 40:899-910.
5. Apanovitch D.M., Slep K.C., Sigler P.B., Dohlman H.G. Sst2 is a GTPase-activating protein for Gpa1: Purification and characterization of a cognate RGS-Galpha protein pair in yeast. Biochemistry 1998, 37:4815-4822.
6. Bacart J., Corbel C., Jockers R., Bach S., Couturier C. The BRET technology and its application to screening assays. Biotechnology Journal 2008, 3:311-324.
7. Bansal G., Druey K.M., Xie Z. R4 RGS proteins: Regulation of G-protein signaling and beyond. Pharmacology & Therapeutics 2007, 116:473-495.
8. Bender K., Nasrollahzadeh P., Timpert M., Liu B., Pott L., Kienitz M.C. A role for RGS10 in beta-adrenergic modulation of G-protein-activated K+ (GIRK) channel current in rat atrial myocytes. The Journal of Physiology 2008, 586:2049-2060.
9. Benzing T., Kottgen M., Johnson M., Schermer B., Zentgraf H., Walz G., Kim E. Interaction of 14-3-3 protein with regulator of G protein signaling 7 is dynamically regulated by tumor necrosis factor-alpha. The Journal of Biological Chemistry 2002, 277:32954-32962.
10. Berman D.M., Kozasa T., Gilman A.G. The GTPase-activating protein RGS4 stabilizes the transition state for nucleotide hydrolysis. The Journal of Biological Chemistry 1996, 271:27209-27212.
11. Berman D.M., Wilkie T.M., Gilman A.G. GAIP and RGS4 are GTPase-activating proteins for the Gi subfamily of G protein alpha subunits. Cell 1996, 86:445-452.
12. Bernstein L.S., Grillo A.A., Loranger S.S., Linder M.E. RGS4 binds to membranes through an amphipathic alpha-helix. The Journal of Biological Chemistry 2000, 275:18520-18526.
13. Blazer L.L., Neubig R.R. Small molecule protein-protein interaction inhibitors as CNS therapeutic agents: Current progress and future hurdles. Neuropsychopharmacology 2009, 34:126-141.
14. Blazer L.L., Roman D.L., Chung A., Larsen M.J., Greedy B.M., Husbands S.M., Neubig R.R. Reversible, allosteric small-molecule inhibitors of regulator of G protein signaling proteins. Molecular Pharmacology 2010, 78:524-533.
15. Blazer L.L., Roman D.L., Muxlow M.R., Neubig R.R. Use of flow cytometric methods to quantify protein-protein interactions. Current Protocols in Cytometry 2010, 11-15. Chapter 13, Unit 13.11.
16. Blazer L.L., Zhang H., Casey E.M., Husbands S.M., Neubig R.R. A nanomolar-potency small molecule inhibitor of regulator of G protein signaling (RGS) proteins. Biochemistry 2011, 50(15):3181-3192.
17. Blundell J., Hoang C.V., Potts B., Gold S.J., Powell C.M. Motor coordination deficits in mice lacking RGS9. Brain Research 2008, 1190:78-85.
18. Bodenstein J., Sunahara R.K., Neubig R.R. N-terminal residues control proteasomal degradation of RGS2, RGS4, and RGS5 in human embryonic kidney 293 cells. Molecular Pharmacology 2007, 71:1040-1050.
19. Brower C.S., Varshavsky A. Ablation of arginylation in the mouse N-End Rule pathway: Loss of fat, higher metabolic rate, damaged spermatogenesis, and neurological perturbations. PloS One 2009, 4:e7757.
20. Burgon P.G., Lee W.L., Nixon A.B., Peralta E.G., Casey P.J. Phosphorylation and nuclear translocation of a regulator of G protein signaling (RGS10). The Journal of Biological Chemistry 2001, 276:32828-32834.
21. Cao X., Qin J., Xie Y., Khan O., Dowd F., Scofield M., et al. Regulator of G-protein signaling 2 (RGS2) inhibits androgen-independent activation of androgen receptor in prostate cancer cells. Oncogene 2006, 25:3719-3734.
22. Castro-Fernandez C., Janovick J.A., Brothers S.P., Fisher R.A., Ji T.H., Conn P.M. Regulation of RGS3 and RGS10 palmitoylation by GnRH. Endocrinology 2002, 143:1310-1317.
23. Chatterjee T.K., Fisher R.A. Cytoplasmic, nuclear, and golgi localization of RGS proteins. Evidence for N-terminal and RGS domain sequences as intracellular targeting motifs. The Journal of Biological Chemistry 2000, 275:24013-24021.
24. Cheever M.L., Snyder J.T., Gershburg S., Siderovski D.P., Harden T.K., Sondek J. Crystal structure of the multifunctional Gbeta5-RGS9 complex. Nature Structural & Molecular Biology 2008, 15:155-162.
25. Chen C.K., Burns M.E., He W., Wensel T.G., Baylor D.A., Simon M.I. Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9-1. Nature 2000, 403:557-560.
26. Chen C.K., Eversole-Cire P., Zhang H., Mancino V., Chen Y.J., He W., Wensel T.G., Simon M.I. Instability of GGL domain-containing RGS proteins in mice lacking the G protein beta-subunit Gbeta5. Proceedings of the National Academy of Sciences of the United States of America 2003, 100:6604-6609.
27. Chen C., Seow K.T., Guo K., Yaw L.P., Lin S.C. The membrane association domain of RGS16 contains unique amphipathic features that are conserved in RGS4 and RGS5. The Journal of Biological Chemistry 1999, 274:19799-19806.
28. Chen C., Wang H., Fong C.W., Lin S.C. Multiple phosphorylation sites in RGS16 differentially modulate its GAP activity. FEBS Letters 2001, 504:16-22.
29. Cho H., Park C., Hwang I.Y., Han S.B., Schimel D., Despres D., Kehrl J.H. Rgs5 targeting leads to chronic low blood pressure and a lean body habitus. Molecular and Cellular Biology 2008, 28:2590-2597.
30. Cifelli C., Rose R.A., Zhang H., Voigtlaender-Bolz J., Bolz S.S., Backx P.H., Heximer S.P. RGS4 regulates parasympathetic signaling and heart rate control in the sinoatrial node. Circulation Research 2008, 103:527-535.
31. Cunningham M.L., Waldo G.L., Hollinger S., Hepler J.R., Harden T.K. Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling. The Journal of Biological Chemistry 2001, 276:5438-5444.
32. Davydov I.V., Varshavsky A. RGS4 is arginylated and degraded by the N-end rule pathway in vitro. The Journal of Biological Chemistry 2000, 275:22931-22941.
33. De Vries L., Elenko E., Hubler L., Jones T.L., Farquhar M.G. GAIP is membrane-anchored by palmitoylation and interacts with the activated (GTP-bound) form of G alpha i subunits. Proceedings of the National Academy of Sciences of the United States of America 1996, 93:15203-15208.
34. Derrien A., Druey K.M. RGS16 function is regulated by epidermal growth factor receptor-mediated tyrosine phosphorylation. The Journal of Biological Chemistry 2001, 276:48532-48538.
35. Derrien A., Zheng B., Osterhout J.L., Ma Y.C., Milligan G., Farquhar M.G., Druey K.M. Src-mediated RGS16 tyrosine phosphorylation promotes RGS16 stability. The Journal of Biological Chemistry 2003, 278:16107-16116.
36. Dohlman H.G., Apaniesk D., Chen Y., Song J., Nusskern D. Inhibition of G-protein signaling by dominant gain-of-function mutations in Sst2p, a pheromone desensitization factor in Saccharomyces cerevisiae. Molecular and Cellular Biology 1995, 15:3635-3643.
37. Dohlman H.G., Song J., Ma D., Courchesne W.E., Thorner J. Sst2, a negative regulator of pheromone signaling in the yeast Saccharomyces cerevisiae: Expression, localization, and genetic interaction and physical association with Gpa1 (the G-protein alpha subunit). Molecular and Cellular Biology 1996, 16:5194-5209.
38. Drenan R.M., Doupnik C.A., Boyle M.P., Muglia L.J., Huettner J.E., Linder M.E., Blumer K.J. Palmitoylation regulates plasma membrane-nuclear shuttling of R7BP, a novel membrane anchor for the RGS7 family. The Journal of Cell Biology 2005, 169:623-633.
39. Drenan R.M., Doupnik C.A., Jayaraman M., Buchwalter A.L., Kaltenbronn K.M., et al. R7BP augments the function of RGS7*Gbeta5 complexes by a plasma membrane-targeting mechanism. The Journal of Biological Chemistry 2006, 281:28222-28231.
40. Druey K.M., Ugur O., Caron J.M., Chen C.K., Backlund P.S., Jones T.L. Amino-terminal cysteine residues of RGS16 are required for palmitoylation and modulation of Gi- and Gq-mediated signaling. The Journal of Biological Chemistry 1999, 274:18836-18842.
41. Fu Y., Huang X., Piao L., Lopatin A.N., Neubig R.R. Endogenous RGS proteins modulate SA and AV nodal functions in isolated heart: Implications for sick sinus syndrome and AV block. American Journal of Physiology. Heart and Circulatory Physiology 2007, 292:H2532-H2539.
42. Fu Y., Huang X., Zhong H., Mortensen R.M., D'Alecy L.G., Neubig R.R. Endogenous RGS proteins and Galpha subtypes differentially control muscarinic and adenosine-mediated chronotropic effects. Circulation Research 2006, 98:659-666.
43. Gales C., Rebois R.V., Hogue M., Trieu P., Breit A., Hebert T.E., Bouvier M. Real-time monitoring of receptor and G-protein interactions in living cells. Nature Methods 2005, 2:177-184.
44. Glick J.L., Meigs T.E., Miron A., Casey P.J. RGSZ1, a Gz-selective regulator of G protein signaling whose action is sensitive to the phosphorylation state of Gzalpha. The Journal of Biological Chemistry 1998, 273:26008-26013.
45. Gold S.J., Hoang C.V., Potts B.W., Porras G., Pioli E., Kim K.W., et al. RGS9-2 negatively modulates L-3,4-dihydroxyphenylalanine-induced dyskinesia in experimental Parkinson's disease. The Journal of Neuroscience 2007, 27:14338-14348.
46. Gold S.J., Ni Y.G., Dohlman H.G., Nestler E.J. Regulators of G-protein signaling (RGS) proteins: Region-specific expression of nine subtypes in rat brain. The Journal of Neuroscience 1997, 17:8024-8037.
47. Goldenstein B.L., Nelson B.W., Xu K., Luger E.J., Pribula J.A., Wald J.M., et al. Regulator of G protein signaling protein suppression of Galphao protein-mediated alpha2A adrenergic receptor inhibition of mouse hippocampal CA3 epileptiform activity. Molecular Pharmacology 2009, 75:1222-1230.
48. Gu S., Cifelli C., Wang S., Heximer S.P. RGS proteins: Identifying new GAPs in the understanding of blood pressure regulation and cardiovascular function. Clinical Science (London, England) 2009, 116:391-399.
49. Gurley S.B., Griffiths R.C., Mendelsohn M.E., Karas R.H., Coffman T.M. Renal actions of RGS2 control blood pressure. Journal of the American Society of Nephrology 2010, 21:1847-1851.
50. Hajdu-Cronin Y.M., Chen W.J., Patikoglou G., Koelle M.R., Sternberg P.W. Antagonism between G(o)alpha and G(q)alpha in Caenorhabditis elegans: The RGS protein EAT-16 is necessary for G(o)alpha signaling and regulates G(q)alpha activity. Genes & Development 1999, 13:1780-1793.
51. Han M.H., Renthal W., Ring R.H., Rahman Z., Psifogeorgou K., Howland D., et al. Brain region specific actions of regulator of G protein signaling 4 oppose morphine reward and dependence but promote analgesia. Biological Psychiatry 2009, 67(8):761-769.
52. Hershko A., Ciechanover A. The ubiquitin system. Annual Review of Biochemistry 1998, 67:425-479.
53. Heximer S.P., Knutsen R.H., Sun X., Kaltenbronn K.M., Rhee M.H., Peng N., et al. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. The Journal of Clinical Investigation 2003, 111:445-452.
54. Heximer S.P., Lim H., Bernard J.L., Blumer K.J. Mechanisms governing subcellular localization and function of human RGS2. The Journal of Biological Chemistry 2001, 276:14195-14203.
55. Heximer S.P., Watson N., Linder M.E., Blumer K.J., Hepler J.R. RGS2/G0S8 is a selective inhibitor of Gqalpha function. Proceedings of the National Academy of Sciences of the United States of America 1997, 94:14389-14393.
56. Hiol A., Davey P.C., Osterhout J.L., Waheed A.A., Fischer E.R., Chen C.K., et al. Palmitoylation regulates regulators of G-protein signaling (RGS) 16 function. I. Mutation of amino-terminal cysteine residues on RGS16 prevents its targeting to lipid rafts and palmitoylation of an internal cysteine residue. The Journal of Biological Chemistry 2003, 278:19301-19308.
57. Hollinger S., Hepler J.R. Cellular regulation of RGS proteins: Modulators and integrators of G protein signaling. Pharmacological Reviews 2002, 54:527-559.
58. Hooks S.B., Martemyanov K., Zachariou V. A role of RGS proteins in drug addiction. Biochemical Pharmacology 2008, 75:76-84.
59. Hooks S.B., Waldo G.L., Corbitt J., Bodor E.T., Krumins A.M., Harden T.K. RGS6, RGS7, RGS9, and RGS11 stimulate GTPase activity of Gi family G-proteins with differential selectivity and maximal activity. The Journal of Biological Chemistry 2003, 278:10087-10093.
60. Hu G., Jang G.F., Cowan C.W., Wensel T.G., Palczewski K. Phosphorylation of RGS9-1 by an endogenous protein kinase in rod outer segments. The Journal of Biological Chemistry 2001, 276:22287-22295.
61. Huang X., Charbeneau R.A., Fu Y., Kaur K., Gerin I., MacDougald O.A., Neubig R.R. Resistance to diet-induced obesity and improved insulin sensitivity in mice with a regulator of G protein signaling-insensitive G184S Gnai2 allele. Diabetes 2008, 57:77-85.
62. Huang C., Liu S., Miller R.T. Role of p115RhoGEF in the regulation of extracellular Ca(2+)-induced choline kinase activation and prostate cancer cell proliferation. International Journal of Cancer 2010, 128(12):2833-2842.
63. Hunt T.W., Fields T.A., Casey P.J., Peralta E.G. RGS10 is a selective activator of G alpha i GTPase activity. Nature 1996, 383:175-177.
64. Iankova I., Chavey C., Clape C., Colomer C., Guerineau N.C., Grillet N., et al. Regulator of G protein signaling-4 controls fatty acid and glucose homeostasis. Endocrinology 2008, 149:5706-5712.
65. Ishii M., Fujita S., Yamada M., Hosaka Y., Kurachi Y. Phosphatidylinositol 3,4,5-trisphosphate and Ca2+/calmodulin competitively bind to the regulators of G-protein-signalling (RGS) domain of RGS4 and reciprocally regulate its action. The Biochemical Journal 2005, 385:65-73.
66. Ishii M., Ikushima M., Kurachi Y. In vivo interaction between RGS4 and calmodulin visualized with FRET techniques: Possible involvement of lipid raft. Biochemical and Biophysical Research Communications 2005, 338:839-846.
67. Jayaraman M., Zhou H., Jia L., Cain M.D., Blumer K.J. R9AP and R7BP: Traffic cops for the RGS7 family in phototransduction and neuronal GPCR signaling. Trends in Pharmacological Sciences 2009, 30:17-24.
68. Jin Y., Zhong H., Omnaas J.R., Neubig R.R., Mosberg H.I. Structure-based design, synthesis, and pharmacologic evaluation of peptide RGS4 inhibitors. The Journal of Peptide Research 2004, 63:141-146.
69. Johnson E.N., Seasholtz T.M., Waheed A.A., Kreutz B., Suzuki N., Kozasa T., et al. RGS16 inhibits signalling through the G alpha 13-Rho axis. Nature Cell Biology 2003, 5:1095-1103.
70. Kimple R.J., De Vries L., Tronchere H., Behe C.I., Morris R.A., Gist Farquhar M., Siderovski D.P. RGS12 and RGS14 GoLoco motifs are G alpha(i) interaction sites with guanine nucleotide dissociation inhibitor activity. The Journal of Biological Chemistry 2001, 276:29275-29281.
71. Koelle M.R., Horvitz H.R. EGL-10 regulates G protein signaling in the C. elegans nervous system and shares a conserved domain with many mammalian proteins. Cell 1996, 84:115-125.
72. Kovoor A., Seyffarth P., Ebert J., Barghshoon S., Chen C.K., Schwarz S., et al. D2 dopamine receptors colocalize regulator of G-protein signaling 9-2 (RGS9-2) via the RGS9 DEP domain, and RGS9 knock-out mice develop dyskinesias associated with dopamine pathways. The Journal of Neuroscience 2005, 25:2157-2165.
73. Kwon Y.T., Kashina A.S., Davydov I.V., Hu R.G., An J.Y., Seo J.W., et al. An essential role of N-terminal arginylation in cardiovascular development. Science 2002, 297:96-99.
74. Lan K.L., Sarvazyan N.A., Taussig R., Mackenzie R.G., DiBello P.R., Dohlman H.G., Neubig R.R. A point mutation in Galphao and Galphai1 blocks interaction with regulator of G protein signaling proteins. The Journal of Biological Chemistry 1998, 273:12794-12797.
75. Lan K.L., Zhong H., Nanamori M., Neubig R.R. Rapid kinetics of regulator of G-protein signaling (RGS)-mediated Galphai and Galphao deactivation. Galpha specificity of RGS4 AND RGS7. The Journal of Biological Chemistry 2000, 275:33497-33503.
76. Lee M.J., Tasaki T., Moroi K., An J.Y., Kimura S., Davydov I.V., Kwon Y.T. RGS4 and RGS5 are in vivo substrates of the N-end rule pathway. Proceedings of the National Academy of Sciences of the United States of America 2005, 102:15030-15035.
77. Leifert W.R., Bailey K., Cooper T.H., Aloia A.L., Glatz R.V., McMurchie E.J. Measurement of heterotrimeric G-protein and regulators of G-protein signaling interactions by time-resolved fluorescence resonance energy transfer. Analytical Biochemistry 2006, 355:201-212.
78. Linder M.E., Deschenes R.J. Palmitoylation: Policing protein stability and traffic. Nature Reviews. Molecular Cell Biology 2007, 8:74-84.
79. Lohse M.J., Nikolaev V.O., Hein P., Hoffmann C., Vilardaga J.P., Bunemann M. Optical techniques to analyze real-time activation and signaling of G-protein-coupled receptors. Trends in Pharmacological Sciences 2008, 29:159-165.
80. Luo X., Popov S., Bera A.K., Wilkie T.M., Muallem S. RGS proteins provide biochemical control of agonist-evoked [Ca2+]i oscillations. Molecular Cell 2001, 7:651-660.
81. Muallem S., Wilkie T.M. G protein-dependent Ca2+ signaling complexes in polarized cells. Cell Calcium 1999, 26:173-180.
82. Neubig R.R., Siderovski D.P. Regulators of G-protein signalling as new central nervous system drug targets. Nature Reviews. Drug Discovery 2002, 1:187-197.
83. Nguyen C.H., Ming H., Zhao P., Hugendubler L., Gros R., Kimball S.R., Chidiac P. Translational control by RGS2. The Journal of Cell Biology 2009, 186:755-765.
84. Ni J., Qu L., Yang H., Wang M., Huang Y. Palmitoylation and its effect on the GTPase-activating activity and conformation of RGS2. The International Journal of Biochemistry & Cell Biology 2006, 38:2209-2218.
85. Nunn C., Mao H., Chidiac P., Albert P.R. RGS17/RGSZ2 and the RZ/A family of regulators of G-protein signaling. Seminars in Cell & Developmental Biology 2006, 17:390-399.
86. Ogier-Denis E., Pattingre S., El Benna J., Codogno P. Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. The Journal of Biological Chemistry 2000, 275:39090-39095.
87. Oliveira-Dos-Santos A.J., Matsumoto G., Snow B.E., Bai D., Houston F.P., Whishaw I.Q., et al. Regulation of T cell activation, anxiety, and male aggression by RGS2. Proceedings of the National Academy of Sciences of the United States of America 2000, 97:12272-12277.
88. Osterhout J.L., Waheed A.A., Hiol A., Ward R.J., Davey P.C., Nini L., et al. Palmitoylation regulates regulator of G-protein signaling (RGS) 16 function. II. Palmitoylation of a cysteine residue in the RGS box is critical for RGS16 GTPase accelerating activity and regulation of Gi-coupled signalling. The Journal of Biological Chemistry 2003, 278:19309-19316.
89. Pfleger K.D., Eidne K.A. Illuminating insights into protein-protein interactions using bioluminescence resonance energy transfer (BRET). Nature Methods 2006, 3:165-174.
90. Popov S.G., Krishna U.M., Falck J.R., Wilkie T.M. Ca2+/calmodulin reverses phosphatidylinositol 3,4,5-trisphosphate-dependent inhibition of regulators of G protein-signaling GTPase-activating protein activity. The Journal of Biological Chemistry 2000, 275:18962-18968.
91. Psifogeorgou K., Papakosta P., Russo S.J., Neve R.L., Kardassis D., Gold S.J., Zachariou V. RGS9-2 is a negative modulator of mu-opioid receptor function. Journal of Neurochemistry 2007, 103:617-625.
92. Rahman Z., Schwarz J., Gold S.J., Zachariou V., Wein M.N., Choi K.H., et al. RGS9 modulates dopamine signaling in the basal ganglia. Neuron 2003, 38:941-952.
93. Roman D.L., Blazer L.L., Monroy C.A., Neubig R.R. Allosteric inhibition of the regulator of G protein signaling-Galpha protein-protein interaction by CCG-4986. Molecular Pharmacology 2010, 78:360-365.
94. Roman D.L., Ota S., Neubig R.R. Polyplexed flow cytometry protein interaction assay: A novel high-throughput screening paradigm for RGS protein inhibitors. Journal of Biomolecular Screening 2009, 14(6):610-619.
95. Roman D.L., Talbot J.N., Roof R.A., Sunahara R.K., Traynor J.R., Neubig R.R. Identification of small-molecule inhibitors of RGS4 using a high-throughput flow cytometry protein interaction assay. Molecular Pharmacology 2007, 71:169-175.
96. Roof R.A., Jin Y., Roman D.L., Sunahara R.K., Ishii M., Mosberg H.I., Neubig R.R. Mechanism of action and structural requirements of constrained peptide inhibitors of RGS proteins. Chemical Biology & Drug Design 2006, 67:266-274.
97. Roof R.A., Roman D.L., Clements S.T., Sobczyk-Kojiro K., Blazer L.L., Ota S., Mosberg H.I., Neubig R.R. A covalent peptide inhibitor of RGS4 identified in a focused one-bead, one compound library screen. BMC Pharmacology 2009, 9:9.
98. Roof R.A., Sobczyk-Kojiro K., Turbiak A.J., Roman D.L., Pogozheva I.D., Blazer L.L., Neubig R.R., Mosberg H.I. Novel peptide ligands of RGS4 from a focused one-bead, one-compound library. Chemical Biology & Drug Design 2008, 72:111-119.
99. Rose J.J., Taylor J.B., Shi J., Cockett M.I., Jones P.G., Hepler J.R. RGS7 is palmitoylated and exists as biochemically distinct forms. Journal of Neurochemistry 2000, 75:2103-2112.
100. Ross E.M., Wilkie T.M. GTPase-activating proteins for heterotrimeric G proteins: Regulators of G protein signaling (RGS) and RGS-like proteins. Annual Review of Biochemistry 2000, 69:795-827.
101. Roy A.A., Baragli A., Bernstein L.S., Hepler J.R., Hebert T.E., Chidiac P. RGS2 interacts with Gs and adenylyl cyclase in living cells. Cellular Signalling 2006, 18:336-348.
102. Ruiz de Azua I., Scarselli M., Rosemond E., Gautam D., Jou W., Gavrilova O., et al. RGS4 is a negative regulator of insulin release from pancreatic beta-cells in vitro and in vivo. Proceedings of the National Academy of Sciences of the United States of America 2010, 107:7999-8004.
103. Saitoh O., Masuho I., Terakawa I., Nomoto S., Asano T., Kubo Y. Regulator of G protein signaling 8 (RGS8) requires its NH2 terminus for subcellular localization and acute desensitization of G protein-gated K+ channels. The Journal of Biological Chemistry 2001, 276:5052-5058.
104. Salim S., Sinnarajah S., Kehrl J.H., Dessauer C.W. Identification of RGS2 and type V adenylyl cyclase interaction sites. The Journal of Biological Chemistry 2003, 278:15842-15849.
105. Sandiford S.L., Slepak V.Z. The Gbeta5-RGS7 complex selectively inhibits muscarinic M3 receptor signaling via the interaction between the third intracellular loop of the receptor and the DEP domain of RGS7. Biochemistry 2009, 48:2282-2289.
106. Schiff M.L., Siderovski D.P., Jordan J.D., Brothers G., Snow B., De Vries L., et al. Tyrosine-kinase-dependent recruitment of RGS12 to the N-type calcium channel. Nature 2000, 408:723-727.
107. Sethakorn N., Yau D.M., Dulin N.O. Non-canonical functions of RGS proteins. Cellular Signalling 2010, 22:1274-1281.
108. Shuey D.J., Betty M., Jones P.G., Khawaja X.Z., Cockett M.I. RGS7 attenuates signal transduction through the G(alpha q) family of heterotrimeric G proteins in mammalian cells. Journal of Neurochemistry 1998, 70:1964-1972.
109. Siderovski D.P., Willard F.S. The GAPs, GEFs, and GDIs of heterotrimeric G-protein alpha subunits. International Journal of Biological Sciences 2005, 1:51-66.
110. Siedlecki A., Anderson J.R., Jin X., Garbow J.R., Lupu T.S., Muslin A.J. RGS4 controls renal blood flow and inhibits cyclosporine-mediated nephrotoxicity. American Journal of Transplantation 2009, 10(2):231-241.
111. Signarvic R.S., Cierniewska A., Stalker T.J., Fong K.P., Chatterjee M.S., Hess P.R., et al. RGS/Gi2alpha interactions modulate platelet accumulation and thrombus formation at sites of vascular injury. Blood 2010, 116:6092-6100.
112. Sjögren B., Blazer L.L., Neubig R.R. Regulators of G protein signaling proteins as targets for drug discovery. Progress in Molecular Biology and Translational Science 2010, 91:81-119.
113. Sjogren B., Neubig R.R. Thinking outside of the " RGS box" New approaches to therapeutic targeting of regulators of G protein signaling. Molecular Pharmacology 2010, 78:550-557.
114. Snow B.E., Brothers G.M., Siderovski D.P. Molecular cloning of regulators of G-protein signaling family members and characterization of binding specificity of RGS12 PDZ domain. Methods in Enzymology 2002, 344:740-761.
115. Snow B.E., Hall R.A., Krumins A.M., Brothers G.M., Bouchard D., Brothers C.A., et al. GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain. The Journal of Biological Chemistry 1998, 273:17749-17755.
116. Sokal I., Hu G., Liang Y., Mao M., Wensel T.G., Palczewski K. Identification of protein kinase C isozymes responsible for the phosphorylation of photoreceptor-specific RGS9-1 at Ser475. The Journal of Biological Chemistry 2003, 278:8316-8325.
117. Srinivasa S.P., Bernstein L.S., Blumer K.J., Linder M.E. Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae. Proceedings of the National Academy of Sciences of the United States of America 1998, 95:5584-5589.
118. Sun X., Kaltenbronn K.M., Steinberg T.H., Blumer K.J. RGS2 is a mediator of nitric oxide action on blood pressure and vasoconstrictor signaling. Molecular Pharmacology 2005, 67:631-639.
119. Talbot J.N., Jutkiewicz E.M., Graves S.M., Clemans C.F., Nicol M.R., Mortensen R.M., et al. RGS inhibition at G(alpha)i2 selectively potentiates 5-HT1A-mediated antidepressant effects. Proceedings of the National Academy of Sciences of the United States of America 2010, 107:11086-11091.
120. Tang K.M., Wang G.R., Lu P., Karas R.H., Aronovitz M., Heximer S.P., et al. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nature Medicine 2003, 9:1506-1512.
121. Tesmer J.J.G. Structure and function of regulator of G protein signaling homology domains. Molecular Biology of RGS Proteins 2009, 75-113. Elsevier, Amsterdam. R.A. Fisher (Ed.).
122. Tesmer J.J., Berman D.M., Gilman A.G., Sprang S.R. Structure of RGS4 bound to AlF4-activated G(i alpha1): Stabilization of the transition state for GTP hydrolysis. Cell 1997, 89:251-261.
123. Traynor J.R., Neubig R.R. Regulators of G protein signaling & drugs of abuse. Molecular Interventions 2005, 5:30-41.
124. Tu Y., Popov S., Slaughter C., Ross E.M. Palmitoylation of a conserved cysteine in the regulator of G protein signaling (RGS) domain modulates the GTPase-activating activity of RGS4 and RGS10. The Journal of Biological Chemistry 1999, 274:38260-38267.
125. Varshavsky A. The N-end rule: Functions, mysteries, uses. Proceedings of the National Academy of Sciences of the United States of America 1996, 93:12142-12149.
126. Wang Y., Lee Y., Zhang J., Young K.H. Identification of peptides that inhibit regulator of G protein signaling 4 function. Pharmacology 2008, 82:97-104.
127. Watson N., Linder M.E., Druey K.M., Kehrl J.H., Blumer K.J. RGS family members: GTPase-activating proteins for heterotrimeric G-protein alpha-subunits. Nature 1996, 383:172-175.
128. Whittington C.J., Kendall T., Pilling S. Are the SSRIs and atypical antidepressants safe and effective for children and adolescents?. Current Opinion in Psychiatry 2005, 18:21-25.
129. Witherow D.S., Tovey S.C., Wang Q., Willars G.B., Slepak V.Z. G beta 5.RGS7 inhibits G alpha q-mediated signaling via a direct protein-protein interaction. The Journal of Biological Chemistry 2003, 278:21307-21313.
130. Xie Z., Geiger T.R., Johnson E.N., Nyborg J.K., Druey K.M. RGS13 acts as a nuclear repressor of CREB. Molecular Cell 2008, 31:660-670.
131. Xie Y., Wolff D.W., Wei T., Wang B., Deng C., Kirui J.K., et al. Breast cancer migration and invasion depend on proteasome degradation of regulator of G-protein signaling 4. Cancer Research 2009, 69:5743-5751.
132. Xie Z., Yang Z., Druey K.M. Phosphorylation of RGS13 by the cyclic AMP-dependent protein kinase inhibits RGS13 degradation. Journal of Molecular Cell Biology 2010, 2:357-365.
133. Yang H., Zonder J.A., Dou Q.P. Clinical development of novel proteasome inhibitors for cancer treatment. Expert Opinion on Investigational Drugs 2009, 18:957-971.
134. Yost E.A., Mervine S.M., Sabo J.L., Hynes T.R., Berlot C.H. Live cell analysis of G protein beta5 complex formation, function, and targeting. Molecular Pharmacology 2007, 72:812-825.
135. Young K.H., Wang Y., Bender C., Ajit S., Ramirez F., Gilbert A., Nieuwenhuijsen B.W. Yeast-based screening for inhibitors of RGS proteins. Methods in Enzymology 2004, 389:277-301.
136. Zachariou V., Georgescu D., Sanchez N., Rahman Z., DiLeone R., Berton O., et al. Essential role for RGS9 in opiate action. Proceedings of the National Academy of Sciences of the United States of America 2003, 100:13656-13661.
137. Zhong H., Neubig R.R. Regulator of G protein signaling proteins: Novel multifunctional drug targets. The Journal of Pharmacology and Experimental Therapeutics 2001, 297:837-845.
138. Zielinski T., Kimple A.J., Hutsell S.Q., Koeff M.D., Siderovski D.P., Lowery R.G. Two G{alpha}i1 rate-modifying mutations act in concert to allow receptor-independent, steady-state measurements of RGS protein activity. Journal of Biomolecular Screening 2009, 14(10):1195-1206.