RIM1α phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term plasticity or learning

Pascal S. Kaeser, Hyung Bae Kwon, Jacqueline Blundell, Vivien Chevaleyre, Wade Morishita, Robert C. Malenka, Craig M. Powell, Pablo E. Castillo, Thomas C. Südhof

Research output: Contribution to journalArticle

49 Citations (Scopus)

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. RIM1α, 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 RIM1α 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 RIM1αKO mice, RIM1 knockin mice containing the serine-413 substitution exhibit normal learning capabilities. The lack of an effect of the serine-413 mutation of RIM1α is not due to compensation by RIM2α because mice carrying both the serine-413 substitution and a RIM2α deletion still exhibited normal long-term presynaptic plasticity. Thus, phosphorylation of serine-413 of RIM1α 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 RIM1α.

Original languageEnglish (US)
Pages (from-to)14680-14685
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number38
DOIs
StatePublished - Sep 23 2008

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Cyclic AMP-Dependent Protein Kinases
Serine
Phosphorylation
Learning
Synapses
Long-Term Potentiation
Hippocampal Mossy Fibers
14-3-3 Proteins
Alanine
Neurons
Mutation

Keywords

  • Active zone
  • Mossy fiber
  • Neurotransmitter release
  • Rab3
  • Synaptic vesicle

ASJC Scopus subject areas

  • General

Cite this

RIM1α phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term plasticity or learning. / Kaeser, Pascal S.; Kwon, Hyung Bae; Blundell, Jacqueline; Chevaleyre, Vivien; Morishita, Wade; Malenka, Robert C.; Powell, Craig M.; Castillo, Pablo E.; Südhof, Thomas C.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 105, No. 38, 23.09.2008, p. 14680-14685.

Research output: Contribution to journalArticle

Kaeser, Pascal S. ; Kwon, Hyung Bae ; Blundell, Jacqueline ; Chevaleyre, Vivien ; Morishita, Wade ; Malenka, Robert C. ; Powell, Craig M. ; Castillo, Pablo E. ; Südhof, Thomas C. / RIM1α phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term plasticity or learning. In: Proceedings of the National Academy of Sciences of the United States of America. 2008 ; Vol. 105, No. 38. pp. 14680-14685.
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T1 - RIM1α phosphorylation at serine-413 by protein kinase A is not required for presynaptic long-term plasticity or learning

AU - Kaeser, Pascal S.

AU - Kwon, Hyung Bae

AU - Blundell, Jacqueline

AU - Chevaleyre, Vivien

AU - Morishita, Wade

AU - Malenka, Robert C.

AU - Powell, Craig M.

AU - Castillo, Pablo E.

AU - Südhof, Thomas C.

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N2 - 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. RIM1α, 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 RIM1α 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 RIM1αKO mice, RIM1 knockin mice containing the serine-413 substitution exhibit normal learning capabilities. The lack of an effect of the serine-413 mutation of RIM1α is not due to compensation by RIM2α because mice carrying both the serine-413 substitution and a RIM2α deletion still exhibited normal long-term presynaptic plasticity. Thus, phosphorylation of serine-413 of RIM1α 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 RIM1α.

AB - 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. RIM1α, 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 RIM1α 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 RIM1αKO mice, RIM1 knockin mice containing the serine-413 substitution exhibit normal learning capabilities. The lack of an effect of the serine-413 mutation of RIM1α is not due to compensation by RIM2α because mice carrying both the serine-413 substitution and a RIM2α deletion still exhibited normal long-term presynaptic plasticity. Thus, phosphorylation of serine-413 of RIM1α 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 RIM1α.

KW - Active zone

KW - Mossy fiber

KW - Neurotransmitter release

KW - Rab3

KW - Synaptic vesicle

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