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, 6 (1), 39-54

Alcohol Related Changes in Regulation of NMDA Receptor Functions


Alcohol Related Changes in Regulation of NMDA Receptor Functions

József Nagy. Curr Neuropharmacol.


Long-term alcohol exposure may lead to development of alcohol dependence in consequence of altered neurotransmitter functions. Accumulating evidence suggests that the N-methyl-D-aspartate (NMDA) type of glutamate receptors is a particularly important site of ethanol's action. Several studies showed that ethanol potently inhibits NMDA receptors (NMDARs) and prolonged ethanol exposition leads to a compensatory "up-regulation" of NMDAR mediated functions. Therefore, alterations in NMDAR function are supposed to contribute to the development of ethanol tolerance, dependence as well as to the acute and late signs of ethanol withdrawal.A number of publications report alterations in the expression and phosphorylation states of NMDAR subunits, in their interaction with scaffolding proteins or other receptors in consequence of chronic ethanol treatment. Our knowledge on the regulatory processes, which modulate NMDAR functions including factors altering transcription, protein expression and post-translational modifications of NMDAR subunits, as well as those influencing their interactions with different regulatory proteins or other downstream signaling elements are incessantly increasing. The aim of this review is to summarize the complex chain of events supposedly playing a role in the up-regulation of NMDAR functions in consequence of chronic ethanol exposure.

Keywords: Alcohol dependence; NMDA receptor; compartmentalization.; phosphorylation/ dephosphorylation; post-translation modifications; subunit expression.


Fig. (1).Schematic model of NMDA glutamate receptor illustrating multiple regulatory sites.
Fig. (1).Schematic model of NMDA glutamate receptor illustrating multiple regulatory sites.
The NMDA glutamate receptor appears to be comprised of 4 subunits, including 2 NR1 subunits and 2 NR2 subunits. This figure illustrates a receptor with an NR2A subunit (in the rear) and an NR2B subunit (in front). Each subunit contains 4 transmembrane domains (TM1–TM4),of which TM2 constitutes a key element of the Ca2+ pore (Kupper et al., 1996). The TM3 region of the NR1 subunit, and perhaps other subunits, appears to be associated with ethanol binding (Ronald et al., 2001). The N-terminal cassette does not appear to be a binding site for ethanol (Popp et al., 1998) but does contain critical sites for modulation, including Zn2+ and redox agents (NR2A) or protons, polyamines,and ifenprodil (NR2B) (reviewed in the text and in Paoletti et al., 1997, 2000; Choi et al., 2001). The glycine-B (GlyB) sites are located in the extracellular domains. The intracellular cassettes of the NR1 contain the sites at which PKA and PKC phosphorylate and PP1 dephosphorylates this subunit. Yotiao (Y) is an NR1-binding protein. The NR1 subunit also contains a site that attaches this subunit to the cytoskeleton via α-actinin-2. The intracellular domain of the NR2 subunits contain phosphorylation sites for the tyrosine kinases (Fyn and Src),CaM kinase II (CaM KII), and PDZ-containing anchoring proteins (PSD-95, chapsyn-110/PSD-93, and SAP-102) that in turn attach NR2 subunits to the cytoskeleton via other proteins (GKAP, Shank, and cortactin). Modified from Woodward (2000) and Millan (2002).John H. Krystal, Ismene L. Petrakis, Graeme Mason, Louis Trevisan, D. Cyril D’Souza (2003) N-methyl-D-aspartate glutamate receptors nd alcoholism: reward, dependence, treatment, and vulnerability. Pharmacol. Ther., 99 , 79-94).
Fig. (2).NMDAR subunit diversity.
Fig. (2).NMDAR subunit diversity.
(a) Dendrogram of complete amino-acid sequences for rat NMDAR subunits. (b) Representation of NMDAR subunit polypeptides.Black boxes indicate transmembrane domains, and grey boxes show the transmembrane TM2 re-entrant loop. Asterisks denote regions at which alternative splicing takes place. This is best characterized for the NR1 subunit, which has three regions of alternative splicing: the amino-terminal N1 cassette (exon 5); and the carboxy-terminal C1 (exon 21) and C2 (exon 22) cassettes. Splicing at these sites can generate eight distinct isoforms (NRI-1a, -1b, -2a, -2b, -3a, -3b, -4a and -4b). Splicing of the NR2C subunit leads to truncated polypeptides ending after TM1 or TM3. The NR2D subunit can be spliced in the carboxyl terminus, producing a 33-amino-acid insert. Likewise, NR3A splicing leads to a 20-aminoacid insert in the carboxyterminal domain. NR2B, NR2C and NR2D also have splice sites in their 5'-untranslated regions but no splice variants have been reported for NR2A. (Stuart Cull-Candy, Stephen Brickley and Mark Farrant (2001) NMDA receptor subunits: diversity, development and disease.Curr. Opin. Neurobiol., 11, 327-335).
Fig. (3).Potential sites for ligand binding at NMDARs.
Fig. (3).Potential sites for ligand binding at NMDARs.
Most NMDAR are believed to assemble as tetramers, associating two NR1 and two NR2 subunits in a ‘dimer of dimers’ quaternary architecture.For clarity, only one of the two NR1/NR2 heterodimers is shown. The extracellular region of each subunit is made up of a tandem of bilobate ‘Venus-flytrap’ domains, the NTD and the ABD. In the extracellular region, the subunits dimerize at the level of the ABDs and probably also at the level of the NTDs. The NR2 ABD binds glutamate, whereas the NR1 ABD binds the co-agonist glycine (or D-serine).White arrows indicate binding sites for competitive agonists and antagonists. Thick orange arrows indicate sites known to bind allosteric modulators such as endogenous zinc (NR2A and NR2B NTDs) or ifenprodil-like compounds (NR2B NTDs), both acting as non-competitive antagonists. The ion-channel domain also forms binding sites for pore blockers such as endogenous Mg2+, MK-801, memantine or ketamine,acting as uncompetitive antagonists. Thin orange arrows indicate putative modulatory sites, which can bind either positive or negative allosteric modulators. The only known NMDAR antagonists that display strong subunit selectivity are the NR2 NTD ligands Zn2+, which selectively inhibits NR2A-containing receptors at nanomolar concentrations, and ifenprodil-like compounds, which selectively inhibit NR2Bcontaining receptors. (Pierre Paoletti and Jacques Neyton (2007) NMDA receptor subunits: function and pharmacology. Curr. Opin. Pharmacol., 7, 39-47).
Fig. (4).Phosphorylation sites of NMDAR subunits.
Fig. (4).Phosphorylation sites of NMDAR subunits.
The N-methyl-D-aspartate (NMDA) receptor subunits are phosphorylated on serine and tyrosine residues. Depicted are the amino acid sequences of the cytoplasmic tails of rat NR1, NR2A, and NR2B subunits. The N-terminus faces the membrane, and the C terminus is facing inward. The kinase is depicted on the top of each rectangle, and the amino acid residue is depicted at the bottom. PKC, protein kinase C;PKA, protein kinase A. (Adapted from: Ron, D. (2004) Signaling Cascades Regulating NMDA Receptor Sensitivity to Ethanol. Neuroscientist, 10(4), 325-336.)

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