title: Effects of the Ras homolog Rhes on Akt/protein kinase B and glycogen synthase kinase 3 phosphorylation in striatum.
abstract: G protein-coupled receptors (GPCR) signal not only through heterotrimeric G proteins, but also through alternate pathways. Thus, dopamine D2 receptors in the striatum signal through Gαi/o and also by promoting formation of a multi-protein complex containing β-arrestin2, protein phosphatase 2A (PP2A), and Akt in order to dephosphorylate Akt. Lithium, on the other hand, disrupts this complex to increase Akt phosphorylation. Rhes is a striatally enriched GTP-binding protein that has been shown to inhibit dopamine receptor-mediated behavior and signaling through heterotrimeric G proteins. Therefore, our objective was to test whether Rhes similarly affects signaling through the Akt/GSK3 pathway in the striatum. Rhes(-/-) mice showed basally increased Akt and GSK3β phosphorylation relative to rhes(+/+) mice that was not further enhanced by lithium treatment. Furthermore, they responded to the D1/D2 agonist apomorphine with increased Akt and GSK3 phosphorylation. Co-immunoprecipitation experiments revealed that apomorphine treatment recruits PP 2A-C to Akt in both rhes(+/+) and rhes(-/-) mice. Lithium did not disrupt their interaction in rhes(-/-) mice as there was little basal interaction. Rhes co-immunoprecipitated with β-arrestins, suggesting that it is integral to the multi-protein complex. Thus, Rhes is necessary for Akt dephosphorylation by the striatal multi-protein complex, and in its absence, a lithium-treated phenotype results.
authors: Neuroscience Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. lhar14@lsuhsc.edu
authors: L M
authors: LM
authors: Harrison
authors: S H
authors: SH
authors: Muller
authors: D
authors: D
authors: Spano
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003342:Corpus Striatum / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D047468:Immunoprecipitation; D018021:Lithium Chloride / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse; D018021:Lithium Chloride
references: Nat Neurosci. 2011 Dec 18;15(2):191-3
references: 22179112
references: J Biol Chem. 2010 Jul 2;285(27):20428-32
references: 20424159
references: Brain Res. 2008 Dec 15;1245:16-25
references: 18929545
references: Annu Rev Pharmacol Toxicol. 1998;38:289-319
references: 9597157
references: Cell. 2005 Jul 29;122(2):261-73
references: 16051150
references: Oncogene. 2004 Jan 15;23(2):559-68
references: 14724584
references: Neurosci Lett. 2012 Jul 19;521(2):142-7
references: 22683505
references: J Neurosci Res. 1999 Sep 15;57(6):782-8
references: 10467249
references: Cell. 2008 Jan 11;132(1):125-36
references: 18191226
references: Mol Cell Biol. 2004 Jul;24(13):5788-96
references: 15199135
references: Nat Genet. 2004 Feb;36(2):131-7
references: 14745448
references: Cell Mol Neurobiol. 2012 Aug;32(6):907-18
references: 22450871
references: EMBO J. 1990 Aug;9(8):2431-8
references: 2164470
references: J Biol Chem. 2006 Jan 13;281(2):1261-73
references: 16280323
references: J Neurosci. 2004 Jul 28;24(30):6791-8
references: 15282284
references: Neuropharmacology. 2011 Jun;60(7-8):1187-92
references: 21044641
references: Mol Cell Neurosci. 2008 Feb;37(2):335-45
references: 18035555
references: Trends Pharmacol Sci. 2011 Sep;32(9):521-33
references: 21680031
references: Med J Aust. 1949 Sep 3;2(10):349-52
references: 18142718
references: Eur J Biochem. 1980 Jun;107(2):519-27
references: 6249596
references: Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8455-9
references: 8710892
references: Curr Biol. 1996 Dec 1;6(12):1664-8
references: 8994831
references: Biol Psychiatry. 2008 Nov 1;64(9):789-96
references: 18571626
references: J Neurosci. 1994 Aug;14(8):4915-26
references: 8046460
references: Trends Biochem Sci. 1992 Oct;17(10):383-7
references: 1455506
references: Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10782-7
references: 12949261
references: Proc Natl Acad Sci U S A. 2011 Jan 18;108(3):1158-63
references: 21187413
references: Neuroscience. 2006;137(2):483-92
references: 16352400
references: Biochem J. 1993 Nov 15;296 ( Pt 1):15-9
references: 8250835
references: Genetics. 2010 Jan;184(1):119-28
references: 19884314
references: Nat Rev Mol Cell Biol. 2008 Jan;9(1):60-71
references: 18043707
references: Science. 2009 Jun 5;324(5932):1327-30
references: 19498170
references: Trends Cell Biol. 2002 Mar;12(3):130-8
references: 11859025
references: J Clin Psychiatry. 2000;61 Suppl 9:35-40
references: 10826659
references: Trends Biochem Sci. 2011 Sep;36(9):457-69
references: 21764321
references: Neuroreport. 2008 Oct 29;19(16):1563-6
references: 18845937
references: Front Mol Neurosci. 2012 Feb 09;5:4
references: 22363258
references: J Neurosci. 2007 Jan 24;27(4):881-5
references: 17251429
references: Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13656-61
references: 18768802
references: J Neurosci Res. 2011 Jun;89(6):874-82
references: 21374700
references: Proc Natl Acad Sci U S A. 2004 Apr 6;101(14):5099-104
references: 15044694
references: Nature. 1995 Dec 21-28;378(6559):785-9
references: 8524413
references: Am J Physiol Cell Physiol. 2008 Nov;295(5):C1417-26
references: 18815223
references: Nature. 1971 Jul 30;232(5309):336-8
references: 5106744