NMDA receptors splice variants

The NMDA receptor has a heteromeric structure composed of two subunit types NRl and NR2, the latter having four subunits (NR2A-NR2D) (Fig. 10.2). Molecular genetic techniques have demonstrated that native NMDA receptors are likely to be composed of a combination of the NRl subunit (which can exist in eight different splice variants) and one or more of the four NR2 subunits which are the main determinants of functional diversity among the NMDA receptors (see Chapter 3 for further details). It has been shown that there are distinct developmental and spatial expression patterns of NMDA receptor NRl subunit splice variants and NR2 receptor subunits in the CNS. 

Hollmann, M., Boulter, J., Maron, C Beasley, L Sullivan, J., Pecht, G., and Heinemann, S. (1993) Zinc potentiates agonist-induced currents at certain splice variants of the NMDA receptor. Neuron 10,943-954. 

From electrophysiological studies with in vitro expressed NMDA subunits in cellular systems, it has been concluded that a conventional NMDA receptor must consist of a mixed combination of NR1 splice variants and NR2A-d subunits in order to have full physiological activity (Monyer et al., 1992). This NR1/NR2 expression pattern has also been reported to be a prerequisite for adequate cell surface expression of NMDA receptors (Mcllhinney et al., 1996). Given the tetrameric stoichiometry, any conventional NMDA receptor might consist of two NR1 and two NR2 subunits. 

NR1 is a component of all native NMDA receptors. The NRI subunit is the glycine binding subunit. It exists as 8 splice variants of a single gene. C-terminal deletion of the NRI subunit causes NMDAR inactivation, changes in downstream... 

Calmodulin (CaM), a Ca2+-binding protein, binds directly to the NR1 subunit of the NMDA receptor in a Ca2+-dependent manner. CaM binding occurs at two distinct sites in the COOH -terminal region of NR1 molecule. One CaM binding site is contained within the spliced Cl exon cassette, whereas the other is located in a region common to all NR1 splice variants (Ehlers et al., 1996). Collective evidence suggests that NMDA receptor function can be modulated by CaM binding to the NR1 subunit and this process may be related to activity-dependent feedback inhibition and Ca2+-dependent inactivation of NMDA receptors. 

Molecular composition NMDA receptors are composed of multiple subunits including at least one NR1 subunit and one or more modulatory subunits from the NR2 (NR2A-NR2D) and/or NR3 (NR3A, NR3B) families. Further eight splice variants have been identified for the NR1 subunits. Each functional NMDA receptor is a heteromultimer, consisting of combinations of NR1, NR2 and/or NR3 subunits. 

Bradley J, Carter SR, Rao VR, Wang J, Finkbeiner S. 2006. Splice variants of the NR1 subunit differentially induce NMDA receptor-dependent gene expression. J Neurosci 26 1065-1076. 

Ehlers MD, Fung ET, O Brien RJ, Huganir RL. 1998. Splice variant-specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments. J Neurosci 18 ... 

PDZ domain suppression of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 28 887-898. 

Standley S, Roche KW, McCallum J, Sans N, Wenthold RJ. 2000. PDZ domain suppression of an ER retention signal in NMDA receptor NRl splice variants. Neuron 28 887-98... 

Fig. 7. The distribution of the NMDA receptor NRl subunit mRNA splice variants in the adult rat brain (X-ray film autoradiographs, horizontal sections). Pan, NRl total mRNA AV, anteroventral thalamic nuclei Cb, cerebellum Cp, caudate putamen Cx, neocortex Dg, denate granule cells ER, entorhinal cortex Hi, hippocampus S, septum smc, sensori-motor cortex T, thalamus. Scale bar, 1.8. mm (Laurie and Seeburg, 1994). See Fig. 6 for explanation of the nomenclature.

Adult Purkinje cells strongly express the NRl gene (Watanabe et al., 1994 Cull-Candy et al., 1998). All the NRl RNA splice variants are found, although NRl-3 (Cl only, see Fig. 6) RNA is at low levels (Laurie et al., 1995). However, according to most reports, adult Purkinje cells do not contain NR2-type subunit mRNA (Watanabe et al., 1994), and indeed have no detectable NMDA receptors (Cull-Candy et al., 1998) nevertheless, two groups have described NR2A mRNA in Purkinje cells (Akazawa et al., 1994 Luque and Richards, 1995). This has still not been resolved. The mismatch in expression between NRl and the NR2 series has been much commented on (Cull-Candy et al., 1998), and it is indeed unusual to find a neuron type with no NMDA response. An outside possibility is that the NRl subunit... 

Johnson RR, Jiang X, Burkhalter A (1996) Regional and laminar differences in synaptic localization of NMDA receptor subunit NRl splice variants in rat visual cortex and hippocampus. J Comp Neurol 568 335-355. 

Mishina, 1995) which are encoded by separate genes and several splice variants for each gene have been described (Danysz and Parsons, 1998). On the basis of morphological studies, it has been shown that NMDA receptors are probably heteromeric assemblies of at least four subunits, with their composition depending from the regional expression in different brain areas (Danysz and Parsons,... 

The NMDA receptors are heterooligomers with two type of subunits. The NRl (or Q subunits exist as a series of at least eight splice variants. The NR2A, B, C, and D (e series) are encoded by four different genes. NRl is regarded as the principal subunit ard NR2 as a regulatory subunit. As with the AMPA receptors the oligomeric NMDA receptors are... 

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