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The effects of NR2 subunit-dependent NMDA receptor kinetics on synaptic transmission and CaMKII activation.

Santucci DM, Raghavachari S - PLoS Comput. Biol. (2008)

Bottom Line: Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities.They also support the conclusion that receptors containing either subtype can drive long-term potentiation.These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.

ABSTRACT
N-Methyl-D-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.

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Time open and receptor failure.(A,B) Upon opening, NR2B-containing receptors stayed open much longer than NR2A-containing receptors. The late decay component time constant was twice as slow, and the weighted time constant of decay (τw) was 10 times slower. (C) The probability of at least one receptor opening, given the number of receptors at the synapse, shows that very few NR2A-containing receptors are needed to provide near-perfect fidelity. (D) Total time open, given the number of receptors. Despite the fact that NR2A-containing receptors open three times as often, NR2B-containing receptors stay open longer, so total time open is only about 50 percent greater for NR2A-containing receptors.
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pcbi-1000208-g002: Time open and receptor failure.(A,B) Upon opening, NR2B-containing receptors stayed open much longer than NR2A-containing receptors. The late decay component time constant was twice as slow, and the weighted time constant of decay (τw) was 10 times slower. (C) The probability of at least one receptor opening, given the number of receptors at the synapse, shows that very few NR2A-containing receptors are needed to provide near-perfect fidelity. (D) Total time open, given the number of receptors. Despite the fact that NR2A-containing receptors open three times as often, NR2B-containing receptors stay open longer, so total time open is only about 50 percent greater for NR2A-containing receptors.

Mentions: NR2A-containing receptors (NR2A-NMDARs) were about three times as likely as NR2B-containing receptors (NR2B-NMDARs) to open in response to the release of a single vesicle (P = 0.73 vs. 0.25). NR2A-NMDARs opened and closed much more quickly, and their peak open probability was more than 10 times greater (0.34 vs. 0.03, Figure 1B–E). On the other hand, NR2B-NMDARs closed more slowly than NR2A-NMDARs (τw = 14.4 vs. 130 msec, τ1 = 12.7 vs. 47.9 msec, τ2 = 505 vs. 964 msec, Figure 2A and 2B). The weighted time constant of decay, τw, was calculated by taking an average of the two time constants (τ1 and τ2) derived from a double exponential fit, weighted by their coefficients in that fit. When NR2B-containing NMDARs opened, they spent twice as much time open (8.0 vs. 16 msec) as NR2A-containing receptors. Thus, the overall time open and average open probability were only about 50 percent greater for NR2A-NMDARs (time open = 5.9 vs. 4.1 msec, Figure 2D).


The effects of NR2 subunit-dependent NMDA receptor kinetics on synaptic transmission and CaMKII activation.

Santucci DM, Raghavachari S - PLoS Comput. Biol. (2008)

Time open and receptor failure.(A,B) Upon opening, NR2B-containing receptors stayed open much longer than NR2A-containing receptors. The late decay component time constant was twice as slow, and the weighted time constant of decay (τw) was 10 times slower. (C) The probability of at least one receptor opening, given the number of receptors at the synapse, shows that very few NR2A-containing receptors are needed to provide near-perfect fidelity. (D) Total time open, given the number of receptors. Despite the fact that NR2A-containing receptors open three times as often, NR2B-containing receptors stay open longer, so total time open is only about 50 percent greater for NR2A-containing receptors.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2563690&req=5

pcbi-1000208-g002: Time open and receptor failure.(A,B) Upon opening, NR2B-containing receptors stayed open much longer than NR2A-containing receptors. The late decay component time constant was twice as slow, and the weighted time constant of decay (τw) was 10 times slower. (C) The probability of at least one receptor opening, given the number of receptors at the synapse, shows that very few NR2A-containing receptors are needed to provide near-perfect fidelity. (D) Total time open, given the number of receptors. Despite the fact that NR2A-containing receptors open three times as often, NR2B-containing receptors stay open longer, so total time open is only about 50 percent greater for NR2A-containing receptors.
Mentions: NR2A-containing receptors (NR2A-NMDARs) were about three times as likely as NR2B-containing receptors (NR2B-NMDARs) to open in response to the release of a single vesicle (P = 0.73 vs. 0.25). NR2A-NMDARs opened and closed much more quickly, and their peak open probability was more than 10 times greater (0.34 vs. 0.03, Figure 1B–E). On the other hand, NR2B-NMDARs closed more slowly than NR2A-NMDARs (τw = 14.4 vs. 130 msec, τ1 = 12.7 vs. 47.9 msec, τ2 = 505 vs. 964 msec, Figure 2A and 2B). The weighted time constant of decay, τw, was calculated by taking an average of the two time constants (τ1 and τ2) derived from a double exponential fit, weighted by their coefficients in that fit. When NR2B-containing NMDARs opened, they spent twice as much time open (8.0 vs. 16 msec) as NR2A-containing receptors. Thus, the overall time open and average open probability were only about 50 percent greater for NR2A-NMDARs (time open = 5.9 vs. 4.1 msec, Figure 2D).

Bottom Line: Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities.They also support the conclusion that receptors containing either subtype can drive long-term potentiation.These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurobiology, Duke University Medical Center, Durham, NC, USA.

ABSTRACT
N-Methyl-D-aspartic acid (NMDA) receptors are widely expressed in the brain and are critical for many forms of synaptic plasticity. Subtypes of the NMDA receptor NR2 subunit are differentially expressed during development; in the forebrain, the NR2B receptor is dominant early in development, and later both NR2A and NR2B are expressed. In heterologous expression systems, NR2A-containing receptors open more reliably and show much faster opening and closing kinetics than do NR2B-containing receptors. However, conflicting data, showing similar open probabilities, exist for receptors expressed in neurons. Similarly, studies of synaptic plasticity have produced divergent results, with some showing that only NR2A-containing receptors can drive long-term potentiation and others showing that either subtype is capable of driving potentiation. In order to address these conflicting results as well as open questions about the number and location of functional receptors in the synapse, we constructed a Monte Carlo model of glutamate release, diffusion, and binding to NMDA receptors and of receptor opening and closing as well as a model of the activation of calcium-calmodulin kinase II, an enzyme critical for induction of synaptic plasticity, by NMDA receptor-mediated calcium influx. Our results suggest that the conflicting data concerning receptor open probabilities can be resolved, with NR2A- and NR2B-containing receptors having very different opening probabilities. They also support the conclusion that receptors containing either subtype can drive long-term potentiation. We also are able to estimate the number of functional receptors at a synapse from experimental data. Finally, in our models, the opening of NR2B-containing receptors is highly dependent on the location of the receptor relative to the site of glutamate release whereas the opening of NR2A-containing receptors is not. These results help to clarify the previous findings and suggest future experiments to address open questions concerning NMDA receptor function.

Show MeSH
Related in: MedlinePlus