Phosphorylation of Ser1166 on GluN2B by PKA Is Critical to Synaptic NMDA Receptor Function and Ca<sup>2+</sup>Signaling in Spines

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

doi:10.1523/jneurosci.4538-13.2014

Cited by 100 publications

(83 citation statements)

References 53 publications

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“…Thus, facilitation of LTP induction by b-AR activation does not require phosphorylation of GluN2A at serine 900 and/or serine 929, suggesting that PKA phosphorylation sites in GluN1 or GluN2B might have a more important role. Consistent with this, b-AR activation increases GluN1 phosphorylation at serine 897 (Murphy et al 2014) and LTP in the hippocampal CA1 region is strongly reduced in "knock-in" mutant mice expressing GluN1 subunits where serine 897 is replaced with a nonphosphorylatable alanine (Li et al 2009). However, these mutants also have deficits in basal NMDAR and AMPA receptor-mediated synaptic transmission and the ability of b-AR activation to facilitate LTP induction has not yet been tested.…”

Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-mentioning

confidence: 53%

“…Importantly, all three of these NMDAR subunits are phosphorylated by PKA at sites that regulate NMDAR ion channel function ( Fig. 2; Leonard and Hell 1997;Tingley et al 1997;Murphy et al 2014). For example, PKA phosphorylation of two sites in the cytoplasmic C-terminal tail of GluN2A subunits (serine 900 and 929) and at serine 1166 in the C-terminus of GluN2B subunits increases channel open probability (Krupp et al 2002;Maki et al 2013;Aman et al 2014).…”

Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-mentioning

confidence: 99%

“…For example, PKA phosphorylation of two sites in the cytoplasmic C-terminal tail of GluN2A subunits (serine 900 and 929) and at serine 1166 in the C-terminus of GluN2B subunits increases channel open probability (Krupp et al 2002;Maki et al 2013;Aman et al 2014). In addition to effects on channel gating, PKA activation also enhances the Ca 2+ permeability of NMDAR ion channels (Skeberdis et al 2006), an effect mediated by phosphorylation of GluN1 subunits at serine 897 and GluN2B subunits at serine 1166 Murphy et al 2014).…”

Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-mentioning

confidence: 99%

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β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

et al. 2015

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Encoding new information in the brain requires changes in synaptic strength. Neuromodulatory transmitters can facilitate synaptic plasticity by modifying the actions and expression of specific signaling cascades, transmitter receptors and their associated signaling complexes, genes, and effector proteins. One critical neuromodulator in the mammalian brain is norepinephrine (NE), which regulates multiple brain functions such as attention, perception, arousal, sleep, learning, and memory. The mammalian hippocampus receives noradrenergic innervation and hippocampal neurons express b-adrenergic receptors, which are known to play important roles in gating the induction of long-lasting forms of synaptic potentiation. These forms of long-term potentiation (LTP) are believed to importantly contribute to long-term storage of spatial and contextual memories in the brain. In this review, we highlight the contributions of noradrenergic signaling in general and b-adrenergic receptors in particular, toward modulating hippocampal LTP. We focus on the roles of NE and b-adrenergic receptors in altering the efficacies of specific signaling molecules such as NMDA and AMPA receptors, protein phosphatases, and translation initiation factors. Also, the roles of b-adrenergic receptors in regulating synaptic "tagging" and "capture" of LTP within synaptic networks of the hippocampus are reviewed. Understanding the molecular and cellular bases of noradrenergic signaling will enrich our grasp of how the brain makes new, enduring memories, and may shed light on credible strategies for improving mental health through treatment of specific disorders linked to perturbed memory processing and dysfunctional noradrenergic synaptic transmission.Synaptic plasticity is a fundamental property of nervous system function. A neuron's ability to alter the strength of its synaptic connections is thought to be the foundation for multiple processes, including learning and memory. Synaptic plasticity is not a single, unitary cellular process, but rather an extremely diverse phenomenon that encompasses many forms and functions. Synapses are dynamic by nature, and only through elucidation of the mechanisms that govern their organization and reorganization can we hope to fully understand how the brain processes and stores information.Acting as potent regulatory agents, neuromodulatory transmitters can significantly alter the properties of neurons at cellular and network levels. Specifically, the modulatory role of the noradrenergic system has been extensively characterized, in part because of the system's anatomically ubiquitous connections. Noradrenergic fibers originate mainly in the locus coeruleus (LC) and project widely throughout the forebrain, with dense innervation of the hippocampus, amygdala, and thalamus (Sara 2009). These connections, especially within the hippocampus, strongly modulate synaptic strength and neural network physiology, which lead to significant alterations in learning, memory, attention, and perception. Noradrenergic receptor signal...

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Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-mentioning

confidence: 53%

Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-mentioning

confidence: 99%

Section: Molecular Mechanisms Underlying the Enhancement Of Ltp By B-mentioning

confidence: 99%

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β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

et al. 2015

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“…However, we found that LTD was not associated with a change in decay kinetics of EPSC NMDA , suggesting no change in NMDAR subunit composition in our experiments. PKA activity has been shown to enhance NMDAR function via phosphorylation of NR1, NR2A, and NR2B subunits (44)(45)(46); thus, a reduction in PKA activity and subsequent dephosphorylation of NMDARs may provide a potential mechanism underlying the decrease in NMDAR currents (44).…”

Section: Discussionmentioning

confidence: 99%

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

Banks

Burroughs

Barker

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Functional connectivity between the hippocampus and prefrontal cortex (PFC) is essential for associative recognition memory and working memory. Disruption of hippocampal-PFC synchrony occurs in schizophrenia, which is characterized by hypofunction of NMDA receptor (NMDAR)-mediated transmission. We demonstrate that activity of dopamine D2-like receptors (D2Rs) leads selectively to long-term depression (LTD) of hippocampal-PFC NMDAR-mediated synaptic transmission. We show that dopamine-dependent LTD of NMDAR-mediated transmission profoundly disrupts normal synaptic transmission between hippocampus and PFC. These results show how dopaminergic activation induces long-term hypofunction of NMDARs, which can contribute to disordered functional connectivity, a characteristic that is a hallmark of psychiatric disorders such as schizophrenia.T he hippocampus to medial prefrontal cortex (PFC) projection is important for executive function and working and long-term memory (1, 2). Glutamatergic neurons of the ventral hippocampal cornu ammonis 1 (CA1) region project directly to layers 2-6 of ipsilateral PFC, and this connection synchronizes PFC and hippocampal activity during particular behavioral conditions (3-5). Disruption of hippocampal-PFC synchrony is associated with cognitive deficits that occur in disorders such as schizophrenia (6). Hippocampal-PFC uncoupling can be achieved by NMDA receptor (NMDAR) antagonism (7), and NMDAR hypofunction is a recognized feature of schizophrenia (8). However, it is unclear, first, how changes in NMDAR function at this synapse may arise, and second, how NMDAR hypofunction affects hippocampal-PFC synaptic transmission.Canonically, NMDARs are considered to contribute little to single synaptic events, but the slow kinetics of NMDARs contribute to maintaining depolarization, leading to the generation of bursts of action potentials (9-13). Furthermore, NMDARs coordinate spike timing relative to the phase of field potential oscillations (14, 15). NMDAR transmission itself undergoes synaptic plasticity (16,17), and this can have a profound effect on sustained depolarization, burst firing, synaptic integration, and metaplasticity (9,11,18,19). In PFC, NMDARs are oppositely regulated by dopamine receptors; D1-like receptors (D1Rs) potentiate and D2-like receptors (D2Rs) depress NMDAR currents (20). Interestingly, NMDAR hypofunction (8, 21) and dopamine D2 receptor activity (22) are potentially converging mechanisms contributing to schizophrenia (23).We now examine the contribution of NMDARs to transmission at the hippocampal-PFC synapse. We show that NMDAR activity provides sustained depolarization that can trigger action potentials during bursts of hippocampal input to PFC. We next demonstrate that dopamine D2 receptor-dependent long-term depression (LTD) of NMDAR transmission profoundly attenuates summation of synaptic transmission and neuronal firing at the hippocampal-PFC input. These findings allow for a mechanistic understanding of how alterations in dopamine and NMDAR function can lead t...

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“…NMDAR functions are tightly and finely modulated by the counterbalanced activity of protein-tyrosine kinases and tyrosine phosphatases (5)(6)(7)(8). Regulation of NMDARs by phosphorylation is involved in versatile cellular processes, such as channel kinetics, receptor trafficking and location, and proteinprotein interactions (9).…”

Section: N-methyl-d-aspartate Receptors (Nmdars)mentioning

confidence: 99%

Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-d-aspartate (NMDA) Receptors

Fang

et al. 2015

Journal of Biological Chemistry

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Phosphorylation of Ser1166 on GluN2B by PKA Is Critical to Synaptic NMDA Receptor Function and Ca²⁺Signaling in Spines

Cited by 100 publications

References 53 publications

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-d-aspartate (NMDA) Receptors

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Phosphorylation of Ser1166 on GluN2B by PKA Is Critical to Synaptic NMDA Receptor Function and Ca2+Signaling in Spines

Cited by 100 publications

References 53 publications

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

β-Adrenergic receptor signaling and modulation of long-term potentiation in the mammalian hippocampus

Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission

Phosphorylation of Tyrosine 1070 at the GluN2B Subunit Is Regulated by Synaptic Activity and Critical for Surface Expression of N-Methyl-d-aspartate (NMDA) Receptors

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Phosphorylation of Ser1166 on GluN2B by PKA Is Critical to Synaptic NMDA Receptor Function and Ca²⁺Signaling in Spines