Separate Intramolecular Targets for Protein Kinase A Control N-Methyl-d-aspartate Receptor Gating and Ca2+ Permeability

Aman, Teresa K.; Maki, Bruce A.; Ruffino, Thomas J.; Kasperek, Eileen M.; Popescu, Gabriela

doi:10.1074/jbc.m113.537282

Cited by 38 publications

(33 citation statements)

References 48 publications

(70 reference statements)

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“…GluN1 CTD contains PKA phosphorylation sites that, in glutamatergic GluN1/GluN2 receptors, control the receptor’s calcium permeability [51]. To examine whether the C-terminal sequence of GluN1 subunits influences conductance and permeation properties for glycinergic GluN1/GluN3A receptors, we recorded whole-cell currents in response to glycine (0.5 mM) in the absence or presence of 1.8 mM free external Ca 2+ and varied the applied pipette potential between −80 mV and +60 mV in 20 mV increments.…”

Section: Resultsmentioning

confidence: 99%

Residues in the GluN1 C-terminal domain control kinetics and pharmacology of GluN1/GluN3A N -methyl- d -aspartate receptors

2017

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N-methyl-D-aspartate (NMDA) receptors assembled from GluN1 and GluN3 subunits are unique in that they form glycine-gated excitatory channels that are insensitive to glutamate and NMDA. Alternative splicing of the GluN1 subunit mRNA results in eight variants with regulated expression patterns and post translational modifications. Here we investigate the role of residues in the GluN1 C-terminal splicing in receptor gating and modulation. We measured whole-cell currents from recombinant GluN1/GluN3A receptors expressed in HEK293 cells that differed in the sequence of their GluN1 C-terminal tail. We found that these residues controlled the level of steady-state activity and the degree to which activity was facilitated by zinc and protons. Further, we found that the phosphorylation status of sites specific to certain variants can also modulate channel activity. Based on these resutl we suggest that GluN1 C-terminal domain splicing may confer cell-specific and activity-dependent regulation onto the level and pharmacologic sensitivity of GluN1/GluN3A currents.

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Section: Resultsmentioning

confidence: 99%

Residues in the GluN1 C-terminal domain control kinetics and pharmacology of GluN1/GluN3A N -methyl- d -aspartate receptors

2017

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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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“…This pathway has generally been viewed as linking extracellular signals to the synthesis of new proteins, especially of AMPA receptors, as well as to transcription regulation, thus participating in the late phase of LTP consolidation. Another pathway, which has received recent attention is the ability of PKA to phosphorylate various residues in GluN2B and GluN1 subunits of NMDA receptors, thereby regulating their gating properties or calcium permeability (Lau et al, 2009; Aman et al, 2014; Murphy et al, 2014). Finally, it is interesting to note that PKA is also involved in actin filament regulation.…”

Section: The Protein Kinase Cascadesmentioning

confidence: 99%

Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning

et al. 2015

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Since its discovery by Bliss and Lomo, the phenomenon of long-term potentiation (LTP) has been extensively studied, as it was viewed as a potential cellular mechanism of learning and memory. Over the years, many signaling cascades have been implicated in its induction, consolidation and maintenance, raising questions regarding its real significance. Here, we review several of the most commonly studies signaling cascades and discuss how they converge on a common set of mechanisms likely to be involved in the maintenance of LTP. We further argue that the existence of cross-talks between these different signaling cascades can not only account for several discrepancies in the literature, but also account for the existence of different forms of LTP, which can be engaged by different types of stimulus parameters under different experimental conditions. Finally, we discuss how the understanding of the diversity of LTP mechanisms can help us understand the diversity of the types of learning and memory.

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Separate Intramolecular Targets for Protein Kinase A Control N-Methyl-d-aspartate Receptor Gating and Ca2+ Permeability

Cited by 38 publications

References 48 publications

Residues in the GluN1 C-terminal domain control kinetics and pharmacology of GluN1/GluN3A N -methyl- d -aspartate receptors

Residues in the GluN1 C-terminal domain control kinetics and pharmacology of GluN1/GluN3A N -methyl- d -aspartate receptors

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

Multiple cellular cascades participate in long-term potentiation and in hippocampus-dependent learning

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