Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines

Jessica A. Murphy, Ivar S. Stein, C. Geoffrey Lau, Rui T. Peixoto, Teresa K. Aman, Naoki Kaneko, Kelly Aromolaran, Jessica L. Saulnier, Gabriela K. Popescu, Bernardo L. Sabatini, Johannes W. Hell, R. Suzanne Zukin

Research output: Contribution to journalArticle

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Abstract

The NMDA-type glutamate receptor (NMDAR) is essential for synaptogenesis, synaptic plasticity, and higher cognitive function. Emerging evidence indicates that NMDAR Ca2+ permeability is under the control of cAMP/protein kinase A (PKA) signaling. Whereas the functional impact of PKA on NMDAR-dependent Ca2+ signaling is well established, the molecular target remains unknown. Here we identify serine residue 1166 (Ser1166) in the carboxy-terminal tail of the NMDAR subunit GluN2B to be a direct molecular and functional target of PKA phosphorylation critical to NMDAR-dependent Ca2+permeation and Ca2+signaling in spines. Activation of β-adrenergic and D1/D5-dopamine receptors induces Ser1166 phosphorylation. Loss of this single phosphorylation site abolishes PKA-dependent potentiation of NMDARCa2+permeation, synaptic currents, and Ca2+ rises in dendritic spines. Wefurther show that adverse experience in the form of forced swim, but not exposure to fox urine, elicits striking phosphorylation of Ser1166 in vivo, indicating differential impact of different forms of stress. Our data identify a novel molecular and functional target of PKA essential to NMDAR-mediated Ca2+ signaling at synapses and regulated by the emotional response to stress.

Original languageEnglish (US)
Pages (from-to)869-879
Number of pages11
JournalJournal of Neuroscience
Volume34
Issue number3
DOIs
StatePublished - 2014

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Neurotransmitter Receptor
Glutamate Receptors
Cyclic AMP-Dependent Protein Kinases
N-Methyl-D-Aspartate Receptors
Serine
Spine
Phosphorylation
Dopamine D5 Receptors
Dopamine D1 Receptors
Dendritic Spines
Neuronal Plasticity
Adrenergic Agents
Synapses
Cognition
Tail
Permeability
Urine

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines. / Murphy, Jessica A.; Stein, Ivar S.; Geoffrey Lau, C.; Peixoto, Rui T.; Aman, Teresa K.; Kaneko, Naoki; Aromolaran, Kelly; Saulnier, Jessica L.; Popescu, Gabriela K.; Sabatini, Bernardo L.; Hell, Johannes W.; Zukin, R. Suzanne.

In: Journal of Neuroscience, Vol. 34, No. 3, 2014, p. 869-879.

Research output: Contribution to journalArticle

Murphy, JA, Stein, IS, Geoffrey Lau, C, Peixoto, RT, Aman, TK, Kaneko, N, Aromolaran, K, Saulnier, JL, Popescu, GK, Sabatini, BL, Hell, JW & Zukin, RS 2014, 'Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines', Journal of Neuroscience, vol. 34, no. 3, pp. 869-879. https://doi.org/10.1523/JNEUROSCI.4538-13.2014
Murphy, Jessica A. ; Stein, Ivar S. ; Geoffrey Lau, C. ; Peixoto, Rui T. ; Aman, Teresa K. ; Kaneko, Naoki ; Aromolaran, Kelly ; Saulnier, Jessica L. ; Popescu, Gabriela K. ; Sabatini, Bernardo L. ; Hell, Johannes W. ; Zukin, R. Suzanne. / Phosphorylation of Ser1166 on GluN2B by PKA is critical to synaptic NMDA receptor function and Ca2+ signaling in spines. In: Journal of Neuroscience. 2014 ; Vol. 34, No. 3. pp. 869-879.
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AU - Geoffrey Lau, C.

AU - Peixoto, Rui T.

AU - Aman, Teresa K.

AU - Kaneko, Naoki

AU - Aromolaran, Kelly

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