title: Domain contributions to signaling specificity differences between Ras-guanine nucleotide releasing factor (Ras-GRF) 1 and Ras-GRF2.
abstract: Ras-GRF1 (GRF1) and Ras-GRF2 (GRF2) constitute a family of similar calcium sensors that regulate synaptic plasticity. They are both guanine exchange factors that contain a very similar set of functional domains, including N-terminal pleckstrin homology, coiled-coil, and calmodulin-binding IQ domains and C-terminal Dbl homology Rac-activating domains, Ras-exchange motifs, and CDC25 Ras-activating domains. Nevertheless, they regulate different forms of synaptic plasticity. Although both GRF proteins transduce calcium signals emanating from NMDA-type glutamate receptors in the CA1 region of the hippocampus, GRF1 promotes LTD, whereas GRF2 promotes θ-burst stimulation-induced LTP (TBS-LTP). GRF1 can also mediate high frequency stimulation-induced LTP (HFS-LTP) in mice over 2-months of age, which involves calcium-permeable AMPA-type glutamate receptors. To add to our understanding of how proteins with similar domains can have different functions, WT and various chimeras between GRF1 and GRF2 proteins were tested for their abilities to reconstitute defective LTP and/or LTD in the CA1 hippocampus of Grf1/Grf2 double knock-out mice. These studies revealed a critical role for the GRF2 CDC25 domain in the induction of TBS-LTP by GRF proteins. In contrast, the N-terminal pleckstrin homology and/or coiled-coil domains of GRF1 are key to the induction of HFS-LTP by GRF proteins. Finally, the IQ motif of GRF1 determines whether a GRF protein can induce LTD. Overall, these findings show that for the three forms of synaptic plasticity that are regulated by GRF proteins in the CA1 hippocampus, specificity is encoded in only one or two domains, and a different set of domains for each form of synaptic plasticity.
authors.affiliation: From the Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111 and.
authors.forename: Shan-Xue
authors.initials: SX
authors.lastname: Jin
authors.affiliation: From the Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111 and.
authors.forename: Christopher
authors.initials: C
authors.lastname: Bartolome
authors.affiliation: From the Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111 and.
authors.forename: Junko A
authors.initials: JA
authors.lastname: Arai
authors.affiliation: the Department of Neurobiology and Anatomy, University of Texas, Houston, Texas.
authors.forename: Laurel
authors.initials: L
authors.lastname: Hoffman
authors.affiliation: From the Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111 and.
authors.forename: B Gizem
authors.initials: BG
authors.lastname: Uzturk
authors.affiliation: From the Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111 and.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kumar-Singh
authors.affiliation: the Department of Neurobiology and Anatomy, University of Texas, Houston, Texas.
authors.forename: M Neal
authors.initials: MN
authors.lastname: Waxham
authors.affiliation: From the Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, Massachusetts 02111 and larry.feig@tufts.edu.
authors.forename: Larry A
authors.initials: LA
authors.lastname: Feig
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D051379:Mice; D015398:Signal Transduction; D020666:ras-GRF1 / Q000378:metabolism*
chemical_list: D020735:Guanine Nucleotide-Releasing Factor 2; D020666:ras-GRF1
keywords: Calcium; Calmodulin (CaM); IQ Motif; LTD; LTP; Mitogen-activated Protein Kinase (MAPK); Ras Protein; Ras-GRF1; Ras-GRF2; Synaptic Plasticity
references.citation: Nat Neurosci. 2000 Nov;3(11):1107-12
references.pmid: 11036267
references.citation: Neuron. 2004 Sep 30;44(1):5-21
references.pmid: 15450156
references.citation: J Biol Chem. 1998 Jul 10;273(28):17579-84
references.pmid: 9651352
references.citation: J Biol Chem. 2004 Jan 16;279(3):2166-75
references.pmid: 14530275
references.citation: Cell. 2002 Aug 23;110(4):443-55
references.pmid: 12202034
references.citation: Neuron. 1999 Nov;24(3):715-26
references.pmid: 10595521
references.citation: J Biol Chem. 2003 May 23;278(21):18833-41
references.pmid: 12531897
references.citation: Hippocampus. 2014 Mar;24(3):315-25
references.pmid: 24174283
references.citation: J Neurosci. 2009 Feb 4;29(5):1496-502
references.pmid: 19193896
references.citation: Biochem Biophys Res Commun. 2005 Aug 26;334(2):674-80
references.pmid: 16009337
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 7;103(45):16692-7
references.pmid: 17075039
references.citation: Biochemistry. 2008 Oct 7;47(40):10587-99
references.pmid: 18795794
references.citation: J Neurosci. 2006 Feb 8;26(6):1721-9
references.pmid: 16467520
references.citation: Front Behav Neurosci. 2011 Dec 28;5:84
references.pmid: 22232579
references.citation: Genes Cancer. 2011 Mar;2(3):306-19
references.pmid: 21779501
references.citation: Mol Cell Biol. 2005 Jun;25(11):4602-14
references.pmid: 15899863
references.citation: Neuron. 2003 Nov 13;40(4):775-84
references.pmid: 14622581
references.citation: Nature. 1995 Aug 10;376(6540):524-7
references.pmid: 7637786
references.citation: Brain Res Mol Brain Res. 1997 Aug;48(1):140-4
references.pmid: 9379834
references.citation: Proc Natl Acad Sci U S A. 2012 Dec 18;109(51):21128-33
references.pmid: 23223532
references.citation: Curr Biol. 2006 Dec 5;16(23):2303-13
references.pmid: 17141611
references.citation: Sci Rep. 2013;3:1392
references.pmid: 23462742
references.citation: J Biol Chem. 1997 Aug 1;272(31):19103-6
references.pmid: 9235897
references.citation: Mol Brain. 2009 Jul 07;2:22
references.pmid: 19583853
references.citation: J Neurosci. 2001 Jan 15;21(2):RC122
references.pmid: 11160456
references.citation: Annu Rev Physiol. 2002;64:289-311
references.pmid: 11826271
references.citation: Biol Psychiatry. 2009 Oct 15;66(8):758-68
references.pmid: 19446794
references.citation: Learn Mem. 2003 Jan-Feb;10(1):26-39
references.pmid: 12551961
references.citation: EMBO J. 2004 Apr 7;23(7):1567-75
references.pmid: 15029245
references.citation: J Biol Chem. 2013 Jul 26;288(30):21703-13
references.pmid: 23766509
references.citation: Front Behav Neurosci. 2011 Dec 06;5:78
references.pmid: 22164138
references.citation: Neuron. 2005 Jun 2;46(5):745-60
references.pmid: 15924861
references.citation: Mol Cell Biol. 2002 Jun;22(12):4073-85
references.pmid: 12024021
references.citation: J Biol Chem. 2014 May 23;289(21):14644-55
references.pmid: 24713697
references.citation: Mol Cell Biol. 1996 Sep;16(9):4888-96
references.pmid: 8756648
references.citation: PLoS One. 2010 Jul 22;5(7):e11732
references.pmid: 20661302