14. N-methyl-D-aspartate receptors (NMDARs) 

 

Number of neuronal responses are facilitated through excitatory glutamatergic receptors i.e. NMDA receptors (NMDARs) (Rajani V et al., 2020).

 

NMDARs have a tetrameric structure composed of one GluN1 and two GluN2 subunits and GluN3 in combination of GluN1 is responsible for configuration of excitatory glycine channels (Grand T et al., 2018) (Rajani V et al., 2020). 

 

According to Rajani V et al., 2020 the “NMDARs structure consist of the N-terminus domain or (NTD), the agonist binding domain or (ABD), the transmembrane domain or (TMD) and the intracellular C-terminus domain or (CTD)” (Rajani V et al., 2020).

 

N-methyl-D-aspartate receptors (NMDARs) References 

1.        Grand, T., Abi Gerges, S., David, M., Diana, M. A. & Paoletti, P. Unmasking GluN1/GluN3A excitatory glycine NMDA receptors. Nat. Commun. 9, 4769 (2018).

2.        Rajani, V., Sengar, A. S. & Salter, M. W. Tripartite signalling by NMDA receptors. Mol. Brain 13, 23 (2020).

 

14.1. NMDAR Signalling Pathway

 

As co-agonists glycine or (D-serine) and glutamate attaches to NMDAR and results in NMDAR extracellular domains conformational changes, consequently a signal transduction takes place through opening of the ion channel and causing a discerning permeability of NMDAR pore for cations such as Na+, K+ and Ca2+ (Rajani V et al., 2020).

 

NMDARs paly a role in activation of calcium related signaling pathways and they are major resources for providing free calcium in cytosol essential for synaptic long- term potentiation (LTP) (Rajani V et al., 2020).

 

A number of kinases are activated by calcium inflow across NMDARs as a result of large inducement of Schaffer collateral participation in CA1 neurons in the hippocampus (Rajani V et al., 2020). Consequently, the aforementioned mechanism also results in downstream AMPA receptors addition into synapse (Hayashi Y et al., 2000 as cited in Rajani V et al., 2020) (Rajani V et al., 2020). 

 

One of the critical kinases calcium/calmodulin kinase II (CaMKII), forms a complex with NMDAR, when it is activated and moved to the post-synaptic density (PSD) (Sanhueza M et al., 2011) (Rajani V et al., 2020). Furthermore, the formation of this complex is important in preservation of synaptic power and suggests that it functions as a molecular switch (Sanhueza M et al., 2011) (Rajani V et al., 2020). This was found as long-term potentiation influence was decreased as a result of the inhibition of the aforementioned complex (Sanhueza M et al., 2011) (Rajani V et al., 2020).

 

There is another process that occurs as a result of induction of NMDARs, which causes steady rise in intracellular calcium (Rajani V et al., 2020). This procedure stems from small inducement of Schaffer collateral participation in CA1 neurons in the hippocampus, which causes NMDAR associated long-term depression (LTD) (Rajani V et al., 2020).

 

It is known that calcium entrance via NMDAR plays role in phosphatase induction, the process that is initiated by aforementioned synaptic depression (Rajani V et al., 2020). This in turn, contains the activation of calcineurin, which is a calcium/calmodulin dependent phosphatase (Rajani V et al., 2020). It is proposed that diverse influence on AMPA receptor trafficking is caused by downstream protein phosphatase 1 (PP1), induced by calcineurin (Beattie E C et al., 2000 as cited in Rajani V et al., 2020) (Mulkey R M et al., 1994 as cited in Rajani V et al., 2020) (Rajani V et al., 2020).

 

NMDAR is also susceptible to the changes in intracellular sodium concentration and regulates the increase of excitatory synaptic transmission (Yu X M and Salter M W., 1998 as cited in Rajani V et al., 2020) (Rajani V et al., 2020). In this way the NMDARs calcium dependent inhibition can be weakened as a consequence of Src tyrosine kinase establishing its sensitivity to sodium concentration (Yu X M et al., 2010) (Yu X M and Salter M W., 1999) (Xin W K et al., 2005) (Rajani V et al., 2020). 

 

NMDAR Signalling Pathway References

 

1.        Beattie, E. C. et al. Regulation of AMPA receptor endocytosis by a signaling mechanism shared with LTD. Nat. Neurosci. 3, 1291–1300 (2000).

2.        Hayashi, Y. et al. Driving AMPA Receptors into Synapses by LTP and CaMKII: Requirement for GluR1 and PDZ Domain Interaction. Science (80-. ). 287, 2262–2267 (2000).

3.        Mulkey, R. M., Endo, S., Shenolikar, S. & Malenka, R. C. Involvement of a calcineurin/ inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369, 486–488 (1994).

4.        Rajani, V., Sengar, A. S. & Salter, M. W. Tripartite signalling by NMDA receptors. Mol. Brain 13, 23 (2020).

5.        Sanhueza, M. et al. Role of the CaMKII/NMDA Receptor Complex in the Maintenance of Synaptic Strength. J. Neurosci. 31, 9170–9178 (2011).

6.        Xin, W.-K. A Functional Interaction of Sodium and Calcium in the Regulation of NMDA Receptor Activity by Remote NMDA Receptors. J. Neurosci. 25, 139–148 (2005).

7.        Yu, X.-M., R. Groveman, B., Fang, X.-Q. & Lin, S.-X. The role of intracellular sodium (Na+) in the regulation of calcium (Ca2+)-mediated signaling and toxicity. Health (Irvine. Calif). 02, 8–15 (2010).

8.        Yu, X.-M. & Salter, M. W. Gain control of NMDA-receptor currents by intracellular sodium. Nature 396, 469–474 (1998).

9.        Yu, X.-M. & Salter, M. W. Src, a molecular switch governing gain control of synaptic transmission mediated by N- methyl- <scp>d</scp> -aspartate receptors. Proc. Natl. Acad. Sci. 96, 7697–7704 (1999).

 

14.2. Glycine Binding Role in NMDAR Signalling      

 

Although signalling through engaging combination of glutamate and glycine binding sites at the same time occurs in NMDAR signaling pathway; this signalling pathway can also takes place through attaching individually to only glycine or glutamate binding sites (Rajani V et al., 2020).

 

In order for ionotropic activity to take place and another non-dependent signalling from ion influx occurs, there is need for increase in concentration of glycine as it primes NMDARs for endocytosis (Rajani V et al., 2020). The process of NMDAR ability to signal through glycine is only feasible as it is suggested that there are two separate affinities of NMDAR for glycine binding site: (i) one with increased affinity for receptor gating (ii) the other with decreased affinity for priming the receptor (Rajani V et al., 2020).

 

Synaptic signaling can be regulated by priming of glycine (Rajani V et al., 2020). This process is known to take place wherever allosteric modulators exist and cause variation in the strength of attachment of glycine/D-serine to GluN1 (Danysz W and Parsons C G., 1998 as cited in Rajani V et al., 2020) (Rajani V et al., 2020).

 

It is also known that in presence of glycine prompting, NMDAR becomes strongly related to AP2 (an adopter protein, which plays a very significant role in intracellular endocytosis), and classifying the induction of the associated downstream endocytic signalling pathway (Rajani V et al., 2020). 

 

Glycine Binding Role in NMDAR Signalling References

 

1.        Danysz, W. & Parsons, C. G. Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol. Rev. 50, 597–664 (1998).

2.        Rajani, V., Sengar, A. S. & Salter, M. W. Tripartite signalling by NMDA receptors. Mol. Brain 13, 23 (2020).

 

14.3. Glutamate Binding Role in NMDAR Signalling

 

The non-ionotropic signalling is induced as a result of prompting the GluN2 activity, which in turn causes a type of long –term depression (LTD) (Nabavi S et al., 2013) (Rajani V et al., 2020).

 

Assembly of LTD in hippocampal slice arrangement proceeds through attachment of  a ligand to the glutamate binding site on GluN2 (Nabavi S et al., 2013) (Rajani V et al., 2020). 

 

The obstruction of glycine site or pore as a result of decrease in the rate of glutamate induction, is the basis for disappearance of spine as a consequence of lack of calcium influx. This process is initially rooted from the effect of aforementioned sequence of events caused by glycine and glutamate on structural plasticity of dendritic spines (Stein I S et al., 2015) (Rajani V et al., 2020).  Furthermore, downstream stimulation of P38 MAPK, which is connected to AMPAR trafficking, is responsible for this synaptic deterioration (Zhu J J et al., 2002) (Rajani V et al., 2020).

 

Glutamate Binding Role in NMDAR Signalling References

 

1.        Nabavi, S. et al. Metabotropic NMDA receptor function is required for NMDA receptor-dependent long-term depression. Proc. Natl. Acad. Sci. 110, 4027–4032 (2013).

2.        Rajani, V., Sengar, A. S. & Salter, M. W. Tripartite signalling by NMDA receptors. Mol. Brain 13, 23 (2020).

3.        Stein, I. S., Gray, J. A. & Zito, K. Non-Ionotropic NMDA Receptor Signaling Drives Activity-Induced Dendritic Spine Shrinkage. J. Neurosci. 35, 12303–12308 (2015).

4.        Zhu, J. J., Qin, Y., Zhao, M., Van Aelst, L. & Malinow, R. Ras and Rap Control AMPA Receptor Trafficking during Synaptic Plasticity. Cell 110, 443–455 (2002).