title: Galanin stimulates neurite outgrowth from sensory neurons by inhibition of Cdc42 and Rho GTPases and activation of cofilin.
abstract: We and others have previously shown that the neuropeptide galanin modulates neurite outgrowth from adult sensory neurons via activation of the second galanin receptor; however, the intracellular signalling pathways that mediate this neuritogenic effect have yet to be elucidated. Here, we demonstrate that galanin decreases the activation state in adult sensory neurons and PC12 cells of Rho and Cdc42 GTPases, both known regulators of filopodial and growth cone motility. Consistent with this, activated levels of Rho and Cdc42 levels are increased in the dorsal root ganglion of adult galanin knockout animals compared with wildtype controls. Furthermore, galanin markedly increases the activation state of cofilin, a downstream effector of many of the small GTPases, in the cell bodies and growth cones of sensory neurons and in PC12 cells. We also demonstrate a reduction in the activation of cofilin, and alteration in growth cone motility, in cultured galanin knockout neurons compared with wildtype controls. These data provide the first evidence that galanin regulates the Rho family of GTPases and cofilin to stimulate growth cone dynamics and neurite outgrowth in sensory neurons. These findings have important therapeutic implications for the treatment of peripheral sensory neuropathies.
authors.affiliation: Schools of Physiology and Pharmacology and Clinical Sciences, University of Bristol, Bristol, UK.
authors.forename: Sally-Ann
authors.initials: SA
authors.lastname: Hobson
authors.forename: Penny A
authors.initials: PA
authors.lastname: Vanderplank
authors.forename: Robert J P
authors.initials: RJ
authors.lastname: Pope
authors.forename: Niall C H
authors.initials: NC
authors.lastname: Kerr
authors.forename: David
authors.initials: D
authors.lastname: Wynick
mesh_terms: D051339:Actin Depolymerizing Factors / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D019004:Galanin / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology; D020439:Growth Cones / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D018715:Microscopy, Video; D016501:Neurites / Q000187:drug effects*; D016716:PC12 Cells; D011554:Pseudopodia / Q000187:drug effects; D051381:Rats; D011984:Sensory Receptor Cells / Q000187:drug effects*; D013268:Stimulation, Chemical; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors*; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000037:antagonists & inhibitors*
chemical_list: D051339:Actin Depolymerizing Factors; D019004:Galanin; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins
keywords: Cdc42; DRG; Rho; cofilin; galanin
references.citation: J Biol Chem. 2007 May 4;282(18):13692-702
references.pmid: 17360713
references.citation: J Cell Biol. 1999 Dec 27;147(7):1519-32
references.pmid: 10613909
references.citation: J Biol Chem. 1995 Dec 8;270(49):29071-4
references.pmid: 7493928
references.citation: Eur J Cell Biol. 2008 Sep;87(8-9):649-67
references.pmid: 18499298
references.citation: Prog Neurobiol. 2007 Jul;82(4):163-201
references.pmid: 17643733
references.citation: EMBO J. 1999 Feb 1;18(3):578-85
references.pmid: 9927417
references.citation: Biochemistry. 2006 Jun 27;45(25):7750-62
references.pmid: 16784226
references.citation: Trends Biochem Sci. 2000 Jan;25(1):19-23
references.pmid: 10637608
references.citation: J Neurobiol. 2000 Jun 15;43(4):352-64
references.pmid: 10861561
references.citation: Neuron. 1997 Sep;19(3):625-34
references.pmid: 9331353
references.citation: Eur J Neurosci. 2008 Jul;28(2):268-78
references.pmid: 18702698
references.citation: Proc Natl Acad Sci U S A. 1976 Jul;73(7):2424-8
references.pmid: 1065897
references.citation: Eur J Neurosci. 2006 Sep;24(6):1555-64
references.pmid: 17004919
references.citation: Tumour Biol. 2012 Dec;33(6):1863-70
references.pmid: 23070684
references.citation: J Neurosci. 1999 Sep 1;19(17):7537-47
references.pmid: 10460260
references.citation: Front Neuroendocrinol. 1992 Oct;13(4):319-43
references.pmid: 1281124
references.citation: J Neurosci. 2000 Apr 1;20(7):2459-69
references.pmid: 10729326
references.citation: J Biol Chem. 1998 Sep 4;273(36):23321-6
references.pmid: 9722565
references.citation: Neurosci Lett. 1987 Dec 29;83(3):217-20
references.pmid: 2450311
references.citation: EMBO J. 2012 Sep 12;31(18):3655-66
references.pmid: 22863780
references.citation: J Neurobiol. 2003 Feb 5;54(2):358-69
references.pmid: 12500311
references.citation: J Neurosci. 2003 Jan 15;23(2):416-21
references.pmid: 12533601
references.citation: Nature. 1998 Jun 25;393(6687):805-9
references.pmid: 9655397
references.citation: J Cell Biol. 1987 Dec;105(6 Pt 1):2817-25
references.pmid: 3320057
references.citation: Nat Rev Neurosci. 2000 Dec;1(3):173-80
references.pmid: 11257905
references.citation: J Neurosci. 2004 Nov 24;24(47):10741-9
references.pmid: 15564592
references.citation: Eur J Neurosci. 2006 Jun;23(11):2937-46
references.pmid: 16819983
references.citation: Proc Natl Acad Sci U S A. 1999 Sep 14;96(19):10905-10
references.pmid: 10485924
references.citation: J Biol Chem. 2002 Jul 26;277(30):27130-4
references.pmid: 12016230
references.citation: J Cell Biol. 1993 Aug;122(3):623-33
references.pmid: 7687605
references.citation: Cell. 1995 Apr 7;81(1):53-62
references.pmid: 7536630
references.citation: Genes Dev. 2012 Aug 1;26(15):1743-57
references.pmid: 22810622
references.citation: J Cell Biol. 1994 Aug;126(3):801-10
references.pmid: 8045941
references.citation: Cell. 1992 Aug 7;70(3):401-10
references.pmid: 1643658
references.citation: Oncogene. 2000 Aug 31;19(37):4199-209
references.pmid: 10980593
references.citation: Science. 1999 Aug 6;285(5429):895-8
references.pmid: 10436159
references.citation: Proc Natl Acad Sci U S A. 2000 Oct 10;97(21):11563-8
references.pmid: 11016970
references.citation: Annu Rev Cell Dev Biol. 1999;15:185-230
references.pmid: 10611961
references.citation: J Neurosci. 2004 May 5;24(18):4363-72
references.pmid: 15128850
references.citation: Prog Neurobiol. 2012 Jul;98(1):16-37
references.pmid: 22609046
references.citation: J Biol Chem. 2003 Apr 18;278(16):13765-74
references.pmid: 12566459
references.citation: J Biol Chem. 2003 Aug 1;278(31):28743-9
references.pmid: 12771155
references.citation: J Biol Chem. 1995 Jul 21;270(29):17582-7
references.pmid: 7615564
references.citation: Nat Neurosci. 2010 Oct;13(10):1208-15
references.pmid: 20835250
references.citation: Mol Cell Biol. 1997 Mar;17(3):1201-11
references.pmid: 9032247
references.citation: J Neurochem. 2006 Nov;99(3):1000-10
references.pmid: 17076662
references.citation: Neuroscience. 1998 Jan;82(2):545-58
references.pmid: 9466460
references.citation: Cell Motil Cytoskeleton. 1998;39(2):172-90
references.pmid: 9484959
references.citation: J Neurobiol. 2006 Feb 5;66(2):103-14
references.pmid: 16215999
references.citation: J Neurosci. 2002 Mar 1;22(5):1794-806
references.pmid: 11880508
references.citation: Genes Dev. 2005 Jan 1;19(1):1-49
references.pmid: 15630019
references.citation: Nature. 1994 Jan 6;367(6458):40-6
references.pmid: 8107774
references.citation: J Neurosci. 2007 Nov 28;27(48):13117-29
references.pmid: 18045906
references.citation: J Neurochem. 2012 Jun;121(6):903-14
references.pmid: 22428561
references.citation: Mol Biol Cell. 2005 Oct;16(10):4473-84
references.pmid: 16014609
references.citation: Nat Cell Biol. 1999 Sep;1(5):253-9
references.pmid: 10559936
references.citation: Biochemistry. 1998 May 12;37(19):6711-7
references.pmid: 9578554
references.citation: Ann N Y Acad Sci. 1998 Dec 21;863:22-47
references.pmid: 9928157
references.citation: Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):1931-6
references.pmid: 18245386
references.citation: EMBO J. 2007 Mar 7;26(5):1410-22
references.pmid: 17318188
references.citation: Biochim Biophys Acta. 2009 Dec;1793(12):1804-10
references.pmid: 19751773
references.citation: J Neurobiol. 2000 Aug;44(2):126-44
references.pmid: 10934317
references.citation: Trends Neurosci. 1994 Jan;17(1):22-30
references.pmid: 7511846
references.citation: Ann Anat. 2011 Jul;193(4):259-66
references.pmid: 21459565
references.citation: Proc Natl Acad Sci U S A. 1994 Oct 11;91(21):9780-3
references.pmid: 7524088
references.citation: Exp Cell Res. 2010 Feb 1;316(3):401-11
references.pmid: 19913013
references.citation: FEBS Lett. 2002 Nov 20;531(3):565-9
references.pmid: 12435612