title: RIM1alpha phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term plasticity or learning.
abstract: Activation of presynaptic cAMP-dependent protein kinase A (PKA) triggers presynaptic long-term plasticity in synapses such as cerebellar parallel fiber and hippocampal mossy fiber synapses. RIM1alpha, a large multidomain protein that forms a scaffold at the presynaptic active zone, is essential for presynaptic long-term plasticity in these synapses and is phosphorylated by PKA at serine-413. Previous studies suggested that phosphorylation of RIM1alpha at serine-413 is required for presynaptic long-term potentiation in parallel fiber synapses formed in vitro by cultured cerebellar neurons and that this type of presynaptic long-term potentiation is mediated by binding of 14-3-3 proteins to phosphorylated serine-413. To test the role of serine-413 phosphorylation in vivo, we have now produced knockin mice in which serine-413 is mutated to alanine. Surprisingly, we find that in these mutant mice, three different forms of presynaptic PKA-dependent long-term plasticity are normal. Furthermore, we observed that in contrast to RIM1alpha KO mice, RIM1 knockin mice containing the serine-413 substitution exhibit normal learning capabilities. The lack of an effect of the serine-413 mutation of RIM1alpha is not due to compensation by RIM2alpha because mice carrying both the serine-413 substitution and a RIM2alpha deletion still exhibited normal long-term presynaptic plasticity. Thus, phosphorylation of serine-413 of RIM1alpha is not essential for PKA-dependent long-term presynaptic plasticity in vivo, suggesting that PKA operates by a different mechanism despite the dependence of long-term presynaptic plasticity on RIM1alpha.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Pascal S
authors.initials: PS
authors.lastname: Kaeser
authors.forename: Hyung-Bae
authors.initials: HB
authors.lastname: Kwon
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Blundell
authors.forename: Vivien
authors.initials: V
authors.lastname: Chevaleyre
authors.forename: Wade
authors.initials: W
authors.lastname: Morishita
authors.forename: Robert C
authors.initials: RC
authors.lastname: Malenka
authors.forename: Craig M
authors.initials: CM
authors.lastname: Powell
authors.forename: Pablo E
authors.initials: PE
authors.lastname: Castillo
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001665:Binding Sites; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007858:Learning / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009412:Nerve Fibers / Q000502:physiology; D009473:Neuronal Plasticity / Q000502:physiology*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000201:enzymology*; D017966:Pyramidal Cells / Q000502:physiology
chemical_list: D048948:14-3-3 Proteins; C491490:Rims1 protein, mouse; D010768:Phosphoserine; D017868:Cyclic AMP-Dependent Protein Kinases; D019204:GTP-Binding Proteins
references.citation: Cell. 2003 Oct 3;115(1):49-60
references.pmid: 14532002
references.citation: Neuron. 1999 Oct;24(2):377-87
references.pmid: 10571231
references.citation: Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14464-9
references.pmid: 12391317
references.citation: Neuropharmacology. 1995 Nov;34(11):1573-9
references.pmid: 8606805
references.citation: Nat Neurosci. 2004 Dec;7(12):1296-8
references.pmid: 15543142
references.citation: Nature. 1997 Aug 7;388(6642):593-8
references.pmid: 9252191
references.citation: Nature. 1995 Sep 14;377(6545):115-8
references.pmid: 7675078
references.citation: Nat Rev Neurosci. 2005 Nov;6(11):863-76
references.pmid: 16261180
references.citation: Sci STKE. 2004 Jul 13;2004(242):re10
references.pmid: 15266103
references.citation: J Biol Chem. 2003 Oct 3;278(40):38301-9
references.pmid: 12871946
references.citation: Neuron. 2003 May 8;38(3):461-72
references.pmid: 12741992
references.citation: Nature. 2002 Jan 17;415(6869):321-6
references.pmid: 11797009
references.citation: Neurosci Lett. 2002 Aug 30;329(2):217-21
references.pmid: 12165416
references.citation: Cell. 1993 Nov 19;75(4):661-70
references.pmid: 7902212
references.citation: Neuron. 1996 Apr;16(4):797-803
references.pmid: 8607997
references.citation: Cell. 1999 Feb 5;96(3):363-74
references.pmid: 10025402
references.citation: Synapse. 1991 Apr;7(4):321-3
references.pmid: 1645891
references.citation: Ann N Y Acad Sci. 1999 Apr 30;868:515-25
references.pmid: 10414328
references.citation: J Biol Chem. 1997 Mar 28;272(13):8441-6
references.pmid: 9079670
references.citation: Nature. 1997 Aug 7;388(6642):590-3
references.pmid: 9252190
references.citation: Nature. 2002 Jan 17;415(6869):327-30
references.pmid: 11797010
references.citation: Prog Neurobiol. 2003 Dec;71(6):401-37
references.pmid: 15013227
references.citation: J Neurophysiol. 1994 Jun;71(6):2552-6
references.pmid: 7931534
references.citation: Neuron. 2004 Apr 8;42(1):143-53
references.pmid: 15066271
references.citation: J Neurosci. 1999 Oct 15;19(20):9090-7
references.pmid: 10516326
references.citation: Science. 2001 Nov 2;294(5544):1030-8
references.pmid: 11691980
references.citation: J Biol Chem. 1997 Dec 12;272(50):31459-64
references.pmid: 9395480
references.citation: Nat Neurosci. 2001 May;4(5):467-75
references.pmid: 11319554
references.citation: J Cell Biol. 2007 Jan 1;176(1):113-24
references.pmid: 17190793
references.citation: J Neurosci. 1999 Jul 15;19(14):5834-46
references.pmid: 10407024
references.citation: J Neurosci. 1999 Dec 1;19(23):10221-7
references.pmid: 10575019
references.citation: Neuron. 2007 Jun 7;54(5):801-12
references.pmid: 17553427
references.citation: EMBO J. 2006 Dec 13;25(24):5852-63
references.pmid: 17124501
references.citation: J Neurosci. 2006 Dec 13;26(50):13089-101
references.pmid: 17167098
references.citation: EMBO J. 1998 Apr 1;17(7):1892-906
references.pmid: 9524113