NMD A receptors

NMD A receptors are selectively activated by A/-methyl-D-aspartate (NMD A) (182). NMD A receptor activation also requires glycine or other co-agonist occupation of an allosteric site. NMDAR-1, -2A, -2B, -2C, and -2D are the five NMD A receptor subunits known. Two forms of NMDAR-1 are generated by alternative splicing. NMDAR-1 proteins form homomeric ionotropic receptors in expression systems and may do so m situ in the CNS. Functional responses, however, are markedly augmented by co-expression of a NMDAR-2 and NMDAR-1 subunits. The kinetic and pharmacological properties of the NMD A receptor are influenced by the particular subunit composition. 

Chen L, Huang LY Sustained potentiation of NMD A receptor-mediated glutamate responses through activation of protein kinase C by a mu opioid. Neuron 7 319-326, 1991... 

There have been a number of observations which show increased excitation and/or reduced inhibition in slices prepared from human epileptic brain tissue. Thus burst discharges can be evoked with stimuli that would not do so in normal animal tissue and these can be blocked by NMD A receptor antagonists. The inhibitory postsynaptic currents (IPSCs) in hippocampal dentate granule cells in slices prepared from temporal lobe epileptic tissue are in fact reduced by stimulation that activates NMDA currents (Isokawa 1996), which are more prolonged than usual and show changes in slope conductance. 

Stelzer, A, Slater, NT and Bruggencate, G (1987) Activation of NMD A receptors blocks GABA ergic innervation in an in vitro model of epilepsy. Nature 326 698-701. 

To date, three of the four FDA-approved medications used in the treatment of the cognitive aspects of AD are acetylcholinesterase inhibitors, which increase overall levels of acetylcholine (the fourth reduces glutamate excitotoxicity via the NMD A receptor). The identification of compounds that reduce inflammation (and thus immune-mediated neuron loss) or increase the levels of acetylcholine are, therefore, also active areas of drug discovery. 

Leeson PD, Carling RW, Moore KW, Moseley AM, Smith JD, Stevenson G, Chan T, Baker FAC, Grimwood S, Kemp JA, Marshall GR, Hoogsteen K (1992) 4-Amido-2-carboxytetra-hydroquinolines, structure-activity relationships for antagonism at the glycine site of the NMD A receptor. J Med Chem 35 1954-1968... 

Figure 1.9 The NMD A receptor, showing the sites of interaction for glutamate (Glu), glycine (Gy), polyamine, Zn2+and Mg2+. Glutamate requires the presence of glycine to open the receptor channel. Polyamine positively modulates, and Zn2+and Mg2+negatively modulate, the opening of the channel. Ketamine and phencyclidine bind to the site labelled PCP.

Dubray, C., Alloui, A., Bardin, L., Rock, E., Mazur, A., Rayssiguier, Y., Eschalier, A., Lavarenne, J. Magnesium deficiency induces an hyperalgesia reversed by the NMD A receptor antagonist MK801, Neuroreport 1997, 8, 1383-1386. 

Collective evidence indicates that mGluR play multiple roles in synaptic plasticity. LTP induction, potentiation of NMD A receptor activity in CA1 neurons, and hippocampal NMDA receptor-dependent LTD involve mGlu receptors. 

The CNS contains a substantial amount of nitric oxide synthase (NOS), which is found within certain classes of neurons. This neuronal NOS is an enzyme activated by calcium-calmodulin, and activation of NMD A receptors, which increases intracellular calcium, results in the generation of nitric oxide. While a physiologic role for nitric oxide has been clearly established for vascular smooth muscle, its role in synaptic transmission and synaptic plasticity remains controversial. 

Kurschner C, Mermelstein PG, Holden WT, Surmeier DJ. CIPP, a novel multivalent PDZ domain protein, selectively interacts with Kir4.0 family members NMD A receptor subunits, neurexins, and neuroligins. Mol Cell Neurosci 1998 11 161-172. 

Faden A. I., DemediukP., PanterS. S., andVinkR. (1989) The role of excitatory amino acids and NMD A receptors in traumatic brain injury. Science 244, 798-800. 

Dopamine Dl receptor activation enhances NMDA-mediated excitatory responses (Cepeda et al., 1993 Cepeda and Levine, 1998). The modulatory actions of dopamine on NMD A receptor mediated responses are reduced in Dl deficient mice (Levine et al., 1996a), supporting a specific role for Dl receptors in enhancement. However, this enhancement involves a complex interplay of actions both on the NMDA receptors and also on the voltage-sensitive calcium channels (VSCC). In particular, the activation of VSCC conductances on the distal dendrites contributes to the enhancement of NMDA currents by dopamine. This mechanism of enhancement involves increased regenerative amplification of synaptic responses by increased VSCC currents (Cepeda et al., 1993, 1998 Cepeda and Levine, 1998). Synaptic responses may also be increased directly by... 

---