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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: 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.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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Receptor kinetics and open probability.(A) The kinetic scheme used to model the receptors. O is the open state; D1 and D2 are desensitized; 0, 1, 2, C1 and C2 are closed. Rate constants, taken from Erreger et al. [21]. and adjusted for temperature, are listed in Table 2. (B,C) Time course of free glutamate concentration in the synaptic cleft. Glutamate concentration peaked and decayed rapidly; the initial τ of decay was ∼60 µsec. (D,E) Examples of single receptor opening and closing in response to glutamate release show that NR2A-containing receptors fail less often, and open and close more rapidly than NR2B-containing receptors. Note that the simulations were carried out at 33°C, so the receptor kinetics are significantly faster than those observed by Erreger et al. [21]. (F,G) Peak open probability was 10 times higher, the early decay component time constant was four times faster, and the probability of success a receptor opening in response to glutamate release (P(success)) was three times greater for NR2A-containing receptors than for NR2B-containing receptors.
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pcbi-1000208-g001: Receptor kinetics and open probability.(A) The kinetic scheme used to model the receptors. O is the open state; D1 and D2 are desensitized; 0, 1, 2, C1 and C2 are closed. Rate constants, taken from Erreger et al. [21]. and adjusted for temperature, are listed in Table 2. (B,C) Time course of free glutamate concentration in the synaptic cleft. Glutamate concentration peaked and decayed rapidly; the initial τ of decay was ∼60 µsec. (D,E) Examples of single receptor opening and closing in response to glutamate release show that NR2A-containing receptors fail less often, and open and close more rapidly than NR2B-containing receptors. Note that the simulations were carried out at 33°C, so the receptor kinetics are significantly faster than those observed by Erreger et al. [21]. (F,G) Peak open probability was 10 times higher, the early decay component time constant was four times faster, and the probability of success a receptor opening in response to glutamate release (P(success)) was three times greater for NR2A-containing receptors than for NR2B-containing receptors.

Mentions: Previous models of NMDA receptors [30]–[33] have been based on the kinetic schemes derived from recordings by Lester and Jahr [29]. Since then, genetic techniques have allowed for a more detailed understanding of the biophysics of NMDA channel gating [21],[34],[35]. Erreger et al. [21] measured single-channel NMDAR kinetics of recombinant diheteromeric NMDARs by expressing NR1 with either NR2A or NR2B. These recordings were used to fit kinetic schemes for each receptor type (Figure 1E) and predicted the average behavior of the channels in response to brief glutamate pulses. The surprising result from this study was that the kinetics of previous models of NMDA receptors were similar to those observed for NR2B-containing receptors, with slow opening, closing and glutamate unbinding. The NR2A-containing receptors, on the other hand, showed markedly faster kinetics, with an on-rate constant for glutamate (∼3×107/M·sec) similar to that of the AMPA receptor (∼2×107/M·sec). These results also implied that NR2A-containing receptors were better suited to sense rapid glutamate transients in the synaptic cleft and would open with a high probability, while NR2B receptors appeared to be tuned to sense ambient levels of glutamate and would open with much lower probability. However, the study used simplified models of glutamate concentration in the cleft and therefore may not inform us about how NMDA channels open in response to synaptically released glutamate.


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

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

Receptor kinetics and open probability.(A) The kinetic scheme used to model the receptors. O is the open state; D1 and D2 are desensitized; 0, 1, 2, C1 and C2 are closed. Rate constants, taken from Erreger et al. [21]. and adjusted for temperature, are listed in Table 2. (B,C) Time course of free glutamate concentration in the synaptic cleft. Glutamate concentration peaked and decayed rapidly; the initial τ of decay was ∼60 µsec. (D,E) Examples of single receptor opening and closing in response to glutamate release show that NR2A-containing receptors fail less often, and open and close more rapidly than NR2B-containing receptors. Note that the simulations were carried out at 33°C, so the receptor kinetics are significantly faster than those observed by Erreger et al. [21]. (F,G) Peak open probability was 10 times higher, the early decay component time constant was four times faster, and the probability of success a receptor opening in response to glutamate release (P(success)) was three times greater for NR2A-containing receptors than for NR2B-containing receptors.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000208-g001: Receptor kinetics and open probability.(A) The kinetic scheme used to model the receptors. O is the open state; D1 and D2 are desensitized; 0, 1, 2, C1 and C2 are closed. Rate constants, taken from Erreger et al. [21]. and adjusted for temperature, are listed in Table 2. (B,C) Time course of free glutamate concentration in the synaptic cleft. Glutamate concentration peaked and decayed rapidly; the initial τ of decay was ∼60 µsec. (D,E) Examples of single receptor opening and closing in response to glutamate release show that NR2A-containing receptors fail less often, and open and close more rapidly than NR2B-containing receptors. Note that the simulations were carried out at 33°C, so the receptor kinetics are significantly faster than those observed by Erreger et al. [21]. (F,G) Peak open probability was 10 times higher, the early decay component time constant was four times faster, and the probability of success a receptor opening in response to glutamate release (P(success)) was three times greater for NR2A-containing receptors than for NR2B-containing receptors.
Mentions: Previous models of NMDA receptors [30]–[33] have been based on the kinetic schemes derived from recordings by Lester and Jahr [29]. Since then, genetic techniques have allowed for a more detailed understanding of the biophysics of NMDA channel gating [21],[34],[35]. Erreger et al. [21] measured single-channel NMDAR kinetics of recombinant diheteromeric NMDARs by expressing NR1 with either NR2A or NR2B. These recordings were used to fit kinetic schemes for each receptor type (Figure 1E) and predicted the average behavior of the channels in response to brief glutamate pulses. The surprising result from this study was that the kinetics of previous models of NMDA receptors were similar to those observed for NR2B-containing receptors, with slow opening, closing and glutamate unbinding. The NR2A-containing receptors, on the other hand, showed markedly faster kinetics, with an on-rate constant for glutamate (∼3×107/M·sec) similar to that of the AMPA receptor (∼2×107/M·sec). These results also implied that NR2A-containing receptors were better suited to sense rapid glutamate transients in the synaptic cleft and would open with a high probability, while NR2B receptors appeared to be tuned to sense ambient levels of glutamate and would open with much lower probability. However, the study used simplified models of glutamate concentration in the cleft and therefore may not inform us about how NMDA channels open in response to synaptically released glutamate.

Bottom Line: 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.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