Polymodal Regulation of NMDA Receptor-Channels

[Channels 1:5, 334-343, September/October 2007]; ©2007 Landes Bioscience

Review

Polymodal Regulation of NMDA Receptor Channels Anna Kloda Boris Martinac David J. Adams*

Abstract

*Correspondence to: David J. Adams; School of Biomedical Sciences; University of Queensland; Brisbane, Queensland QLD 4072 Australia; Tel.: 61.7.3365.1074; Fax: 61.7.3365.4933; Email: [email protected]

OT D

Original manuscript submitted: 08/14/07 Revised manuscript submitted: 09/13/07 Manuscript accepted: 09/13/07

IST RIB

School of Biomedical Sciences; The University of Queensland; Brisbane, Queensland, Australia

UT E

.

Glutamate‑activated N‑methyl‑D‑aspartate (NMDA) receptors are ligand‑gated ion channels, which mediate synaptic transmission, long‑term potentiation, synaptic plasticity and neurodegeneration via conditional Ca2+ signalling. Recent crystallographic studies have focussed on solving the structural determinant of the ligand binding within the core region of NR1 and NR2 subunits. Future structural analysis will help to understand the mechanism of native channel activation and regulation during synaptic transmission. A number of NMDA receptor ligands have been identified which act as positive or negative modulators of receptor function. There is evidence that the lipid bilayer can further regulate the activity of the NMDA receptor channels. Modulators of NMDA receptor function offer the potential for the development of novel therapeutics to target neuro‑ logical disorders associated with this family of glutamate ion channel receptors. Here, we review the recent literature concerning structural and functional properties, as well as the physiological and pathological roles of NMDA receptor channels.

Previously published online as a Channels E-publication: http://www.landesbioscience.com/journals/channels/article/5044

Abbreviations

.D

AMPA, a‑amino‑3‑hydroxy‑5‑methylisoxazole‑4‑propionic acid; ATP, adenosine 5’‑triphosphate; DHA, decosahexanoic acid; ER, endoplasmic reticulum; GABA, g‑aminobutyric acid; K2P, 2‑pore domain potassium channels; LTP, long-term potentia‑ tion; LTD, long term depression; NMDA, N‑methyl‑D‑aspartate; NR1/NR2/NR3, NMDA receptor subunits; PIP2, polyanionic phospholipid; PKC, protein kinase C; PDZ domain, structural domain of signaling proteins; PSD, postsynaptic density protein network; PUFA, omega‑3 polyunsaturated fatty acids; TRPC, transient receptor potential channels; SAKCa, stretch‑activated calcium‑dependent K+ channel; SAP102, synapse associated protein 102

©

20

07

LA

ND

ES

BIO

SC

IEN

CE

NMDA receptors, mechanosensation, bilayer mechanism, fatty acids, protein targeting, signal transduction, glutamate-mediated excitotoxicities

ON

Key words

334

Introduction

The NMDA receptor is an oligomeric cation channel which mediates physiological and pathological processes such as long‑term potentiation (LTP), synaptic plasticity and neurodegeneration via conditional Ca2+ signalling.1‑3 The ionic influx through the open channel pore is consequent to the presynaptic release of glutamate and postsynaptic membrane depolarization, which relieves voltage‑dependent Mg2+ block.4,5 Impairment of the Mg2+ block of NMDA receptors can lead to excessive Ca2+ influx into neurons and the generation of nitric oxide and/or reactive oxygen species. Furthermore, opening of the NMDA receptor is associated with activation of many downstream targets including Ca2+‑dependent enzymes and protein kinase signaling pathways. These biochemical events have been associated with NMDA receptor‑mediated neuronal excitoxicity which underlies many neurodegenerative disorders, neuroinflammation, Alzheimer’s disease, Huntington’s disease, as well as cognitive deficits associated with aging.6‑8 In contrast, diminished function of the NMDA receptor channels has been implicated in pathophysiology of schizophrenia‑like syndrome.9‑12 Several studies suggest that NMDA receptors influence neuronal growth, synaptogenesis and neuronal plasticity as well as fine‑tuning of neuronal connections. It has been reported that immature synapses initially transmit only with NMDA receptors before evidence of AMPA receptor function13‑15 indicating that AMPA receptor gating is not essential for Channels

2007; Vol. 1 Issue 5

Structure and Function of NMDA Receptor-Channels

the activity of NMDA receptors in the early stages of synaptogenesis. At hyperpolarized membrane potentials, NMDA receptor channels are blocked by Mg2+ and AMPA receptor‑triggered membrane depolarization is the main mechanism of removing voltage‑dependent Mg2+ block. Gating of NMDA receptors in the absence of AMPA receptors also indicates that factors other than depolarization (e.g., membrane‑derived signaling) unblocks the NMDA receptor channel during early synaptogenesis. One important physiological implication of this process is that NMDA receptor‑activation during synaptogenesis limits the continuous sprouting of neurons which, in turn, facilitates the onset of AMPA receptor transmission.16 Indeed LTP could be triggered by conversion of silent synapses to functional ones.15 Thus, regulation of Mg2+ block of NMDA receptor channels at these early and functionally silent NMDA receptor synapses could be necessary to ensure transmission fidelity during synaptogenesis when AMPA and presumably other converging inputs are added.

Despite a considerable amount of research on the structure, function and pharmacology of NMDA receptor‑channels, the link between the function of the receptor channel proteins and glutamate‑mediated excitotoxicity remains poorly understood. Many neuroprotective drugs that target NMDA receptor channels have failed clinical trials because of severe side effects due to interference with normal brain function.17 New knowledge about the molecular determinants which influence NMDA receptor channel gating could be instrumental in the discovery of novel agents that target NMDA receptors for the treatment and prevention of neurodegenerative disorders and for further investigation of the role of the receptors in synaptic transmission. The main objectives of this review are: (1) To review the molecular organization and architecture of NMDA receptor channel complexes supported by recent crystallographic studies; (2) To discuss NMDA receptor pharmacology with respect to ligands with therapeutic potential; and (3) To present recent evidence on modulation of NMDA receptor channels by the bilayer mechanism and its potential clinical implications.

The NMDA receptor channel subunits are differentially expressed throughout the brain during development and display different functional properties.3,26‑28 Whilst NR1 subunits are distributed widely throughout the brain,29 the NR2 and NR3 subunits are expressed in different regions of the central nervous system and at different times of development. The NR2A and NR2B subunits are predominantly expressed in the hippocampus, cerebellum and temporal cortex.26,30‑33 During development of the visual cortex, expression of NR2B is predominant in the earlier stages, but switches to NR2A subunit after functional maturation.34 In the cerebellum NR2A subunit is expressed in the Purkinje layer whereas expression of NR2B subunit occurs mostly in the molecular layer.30 The NR2C subunit expression is confined to the cerebellar granule cells and various nuclei of the brainstem.30,32 The NR2D subunit is expressed at its highest levels in the thalamus, midbrain, medulla and spinal cord. The protein expression is elevated during embryonic development but declines during postnatal life.35 The expression of the NR2D subunit persists in interneurons of neostriatum, neocortex and hippocampus.36 In addition to their expression in the central nervous system, the NR1, NR2B and NR2D subunits were identified in the enteric system.37 The NR3A subunit is expressed in the spinal cord, brainstem, hypothalamus, thalamus, CA1 region of hippocampus and amygdala. These subunits are transiently expressed during the first postnatal week, but their expression is attenuated into adulthood.38 In contrast, expression of the NR3B subunit is not developmentally regulated remaining constant during the postnatal and later stages of life. Interestingly, the expression of NR3B subunits is confined mainly to somatic motoneurons of the brain stem and spinal cord.24,39 The heterogeneity of NMDA receptor channels has a further implication in the pathology of Alzheimer’s disease. Progression of Alzheimer’s disease is thought to be dependent on alteration in subunit composition of individual NMDA receptor complexes. These greatly affect the physiological and/or pharmacological profile of the intrinsic ion channel, which subsequently affects neuronal susceptibility to excitoxic death. Indeed several studies have demonstrated changes in NMDA receptor subunits within a specific region of the hippocampus in early stages of the disease.40,41

Subunit Composition and Spatial Distribution of NMDA Receptors

Targeting and Regulation of NMDA Receptor‑Channel Function by Phosphorylation

The complexity of NMDA receptors arise from multiple genes encoding different subunits of the channel and alternative splicing of mRNA which determines variability in subunit composition as well as functional heterogeneity. The ubiquitously expressed NR1 subunit is a product of a single gene encoding eight splice variants, whereas four distinct NR2 subunits (NR2A–NR2D) and two NR3 subunits (A and B) are encoded by distinct genes (reviewed in refs. 18–20). The functional NMDA receptor channel is proposed to operate as a tetramer composed of two NR1 and two NR2 subunits.21 The NR3 subunits can co-assemble with NR1 and NR2 subunits to form heteromeric assemblies gated by glutamate and glycine. However, the coexpression of NR3 subunit with otherwise functional channels (composed of NR1 and NR2 subunits) decreases NMDA receptor currents and Ca2+ permeability.22‑24 In contrast to NR1/NR2 subunit assemblies, the NR1/NR3 complexes have been reported to form excitatory glycine‑gated, Ca2+ impermeable cation channels, which are resistant to Mg2+ block.25

The functional properties of NMDA receptor channels are further regulated via controlled trafficking of the receptor subunits from the endoplasmic reticulum (ER) and the Golgi apparatus to the cell surface. In neuronal cells, a large pool of NR1 subunits is retained in the ER and remains unassembled. Coexpression of NR1 with NR2 and/or NR3 subunits is required to overcome ER retention of homomeric subunits and for efficient transport of heteromeric receptor channels to the cell surface (reviewed in ref. 42). Cell surface expression of functional complexes is further enhanced by the availability of NR1 splice variants lacking the C1 cassette which contains ER retention sequence.43,44 In contrast, the presence of the C2 cassette on NR1 subunits promotes the exit of such splice variants from ER, most likely via interaction with PDZ proteins.43 Furthermore, there is evidence that NMDA receptor trafficking can be regulated through an interaction between a synapse associated protein 102 (SAP102) and a protein of exocyst complex, Sec8, via PDZ binding domains.45 The

Objectives of this Review

www.landesbioscience.com

Channels

335


function of NMDA receptor channels is also differentially regulated by phosphorylation.46 Of particular interest is the involvement of a family of Src protein tyrosine kinases in clathrin mediated endocytosis of NMDA receptors, a process involved in internalization and removal of the receptor proteins from the cell membrane.47 Members of the Src family of protein tyrosine kinases have been reported to upregulate the activity of NMDA receptor channels, whereas tyrosine phosphatases oppose this action.48,49 Thus, participation of NMDA receptors in signaling through tyrosine phosphorylation can be vital for regulation of synaptic strength and plasticity. Excellent coverage of the targeting and regulation of NMDA receptor function by phosphorylation is provided in recent reviews.50,51

Membrane Topology and Crystal Structure of the Ligand Binding Core The transmembrane topology of NMDA receptors predicts an extracellular N‑terminus, followed by three transmembrane domains (TM‑1, TM‑2 and TM‑3). A cytoplasmic reentrant loop (P) lines the channel pore, whereas an extracellular loop links the TM‑2 and TM‑3 domains (Fig. 1A). The cytoplasmic C‑terminus harbours numerous sites for interaction with intracellular proteins.18,52 The pore-lining loop (P) of both subunits harbours an asparagine residue at a position homologous to the Q/R site of AMPA receptors. The RNA editing of the Q/R site controls Ca2+ and Mg2+ permeability which affects single channel conductance and alters the current‑voltage (I‑V) relation of AMPA receptors.53‑55 The site homologous to the Q/R site located on the NMDA receptors formed by asparagine residues strongly affects Mg2+ permeability and channel rectification due to voltage‑dependent Mg2+ block.56,57 These residues are located at the tip of the reentrant loop (P) and thus form the narrowest constriction or the selectivity filter of the channel pore.56,58 The N‑terminus of NR1 and NR2 subunits contains a domain which shares sequence homology with the bacterial leucine/isolucine/ valine‑binding protein (LIVBP).59‑61 The LIVBP domain of NR1 subunit is essential for subunit association, whereas the homologous domain of NR2 subunit is important for modulation and desensitization of NMDA receptor channels.61,62 The agonist binding site is formed by two domains: (i) the N‑terminal S1 segment (which follows the LIVBP domain), and (ii) S2 segment located within the extracellular loop connecting TM‑2 and TM‑3 domains (Fig. 1). These two polypeptides (of 150 amino acids each) show sequence homology with the bacterial glutamine binding protein.63 In the NR1 and NR3 subunits, the agonist binding site binds glycine, whereas glutamate binding occurs within the corresponding region of the NR2 subunit.64‑66 The crystal structure of the ligand binding core of the NR2 subunit associated with glutamate and that of the NR1‑NR2A heterodimer bound to glycine and glutamate, showed that agonists bind within a cleft of a clam‑shell‑like domain formed by S1‑S2 polypeptides (Figs. 1 and 2).64,65 Highly conserved among glutamate receptors, an arginine residue located on helix D provides a coordinate for the binding of the agonist’s a‑carboxyl group.65,67,68 Coordination of ligand a‑amino group in the NR1 subunit is determined by a salt bridge between the carboxylate moieties of D732 residue. Interestingly, in the NR2 subunit the salt bridge is replaced by water mediated hydrogen bonds to residues E413 and Y761, which form a structural interface for the binding of the NMDA molecule. In addition, there is a van der Waals contact between the 336

g‑carboxylate group of glutamate and Y730, which partially accounts for the high affinity binding of glutamate to the NMDA NR2 subunit. Subunit dimerization within the ligand binding cores of NMDA and non-NMDA receptors is highly conserved suggesting a similar gating mechanism.65,68 The closure of each ligand binding core upon binding of the agonist exerts tension on the linkers adjacent to the pore domain leading to channel gating.

Pharmacology of NMDA Receptors The NMDA receptor is an important drug target that influenced a search for molecules acting on this receptor. The main challenge has been the development of competitive antagonists and high affinity channel blockers that can discriminate between different receptor subtypes and multiple binding sites on the NMDA receptor complex. Understanding the mechanisms and identifying sites of regulation of NMDA receptors will help to develop better pharmaceuticals for treatment and prevention of glutamate‑mediated neuronal degeneration, as well as improved analgesic therapies.69 Agonists. Downregulation of NMDA receptor function has been implicated in development of psychotic disorders such as schizophrenia.70 Given that the glycine site is not always saturated, glycine site agonists could be explored as potential antipsychotic agents. In clinical studies, full agonists such as D‑serine significantly improved abnormal behaviour in schizophrenic patients. Other glycine site agonists include 1‑aminocyclopropanecarboxylic acid (ACPC) and S‑hydroxyethylvinyl glycine, whereas the L‑alanine, D‑cycloserine, R+‑3‑amino‑1‑hydroxypyrrolid‑2‑one[+‑HA‑966] and R+‑cis‑b‑m ethyl‑3‑amino‑1‑hydroxypyrrolid‑2‑one compounds act as partial agonist of the glycine site.52,71‑73 Glutamate site agonists of NMDA receptors raised concerns over excitoxicity and thus have not been well explored. Full agonists include N‑methyl‑D‑aspartate, L‑aspartate, quinolinate and homocysteate and a partial agonist cis‑2,3‑piperidinedicarboxylic acid.71,72 Antagonists. A large number of competitive and noncompetitive antagonists of the NMDA receptor have been investigated as potential drugs for treatment of glutamate‑mediated excitoxicity.69,74 Competitive antagonists acting at a glutamate recognition site include (R)‑2‑amin o‑5‑phosphonopentanoate, (±)‑cis‑4‑phosphonomethyl‑2‑piperidine carboxylic acid, D,L‑(E)‑2‑amino‑5‑phosphono‑3‑pentenoic acid, (2‑amino‑4,5‑(1,2‑cyclohexyl))‑7‑phosphonoheptanoic acid, (± phosphonomethyl-decahydroisoquinoline-3‑carboxylic acid, (S)‑a amino‑5‑phosphonomethyl[1,1'‑biphenyl]‑3‑propanoic acid and (S)‑a amino‑5‑phosphonomethyl[1,1':4',1''‑terphenyl]‑3‑propanoic acid. Compounds with NMDA receptor subtype specificity include (1 RS,1'S)‑PEAQX75 and NVP‑AAM077,76 which have high affinity for NR1/NR2A and NR1/NR2B receptor subtypes, respectively. In contrast, (2S*,3R*)‑1‑(phenanthrene‑2‑carbonyl)piperizine‑2,3dicarboxylic acid is a NR2C/NR2D selective antagonist.77 The NR2B subtype selective antagonists include anticonvulsant felbamate,78 conantokin G, a venom peptide isolated from marine cone snail Conus geographus79,80 and a noncompetitive antagonist ifenprodil. The latter compound is a good candidate for treatment of stroke, traumatic brain injury, Alzheimer’s and Parkinson’s diseases.81,82 The ifenprodil site of action has been mapped to the N‑terminal LIVBP‑like domain.83 The advantages of NR2B‑selective antagonists are their improved tolerability and less severe side effects compared to other NMDA receptor antagonists.

Channels



Figure 1. (A) Membrane topology of NMDA receptor showing details of the ligand binding core used for crystallization. S1 and S2 domains are in blue and pink respectively. ATD, N‑terminal domain; CTD, C‑terminal domain; Transmembrane domains TM‑1, TM‑2 and TM‑3 are numbered respectively; P, pore region. (B) Multiple sequence alignment of ligand binding core of NMDA and non-NMDA glutamate receptor homologues. Disulphide bonds are indicated as connecting lines. The determined secondary structure is marked above the sequences as lines for the a‑helices and arrows for b‑strands. Stars (*) denote residues involved in binding of agonist whereas plus (+) symbols indicate antagonist‑binding residues (Reproduced from Furukawa and Gouaux64).


Channels

337


Figure 2. Crystal structure of NR1‑NR2 NMDA receptor ligand binding core region. (A) View of the structure from the side; (B) the top view of the structure; (C) Details of the interaction of glycine within the S1‑S2 region of NR1 subunit. (D) Structural determinants of the glutamate binding within S1‑S2 core of NR2 subunit (Reproduced from Furukawa et al.65).

Zinc is an endogenous NMDA receptor inhibitor that exhibits two effects: (i) a voltage‑dependent block that resembles that of Mg2+; and (ii) a voltage‑independent inhibition, which occurs at a different site.84,85 Although glycine antagonists display poor subtype selectivity due to the location of the binding site on the NR1 subunit, preclinical evidence suggests their potential use in the treatment of chronic pain, drug abuse and as neuroprotective agents.52,86,87 Most of the high‑affinity glycine site selective ligands have been derived from medicinal chemistry and include kynurenic acid, quinolines, quinolones and indoles.88‑90 Several NMDA receptor channel inhibitors can bind to the open states of activated channels. Lower affinity open channel blockers have potential clinical use in the treatment of glutamate‑mediated 338

neurotoxicity due to low interference with physiological NMDA receptor signaling. Compounds such as MK‑801 and phencyclidine are high affinity open channel blockers but, unfortunately, display significant side effects associated with diminished cognitive tasks.91‑93 Compounds with lower affinity such as memantine and ketamine display a better therapeutic profile and memantine has been approved for clinical use for the treatment of Alzheimer’s disease.94,95 Novel open channel blocker compounds with further clinical potential include N‑alkylglycine,96 5‑hydroxytryptamine and several related indolealkylamines.97‑99 Allosteric modulators. Polyamines, spermine and spermidine generally enhance NMDA receptor function by increasing receptor affinity for glycine although a glycine‑independent and NR2B subunit specific mechanism has also been proposed.100,101 Protons

Channels



and Mg2+ have been postulated to be endogenous ligands acting at this site.102 The antibiotic aminoglycoside is an NMDA receptor potentiator partially acting at a polyamine site.103,104 The neurosteroid pregnenolone sulphate potentiates responses of NMDA receptors containing NR2A or NR2B subunits but inhibits responses of NR2C and NR2D‑containing receptor channels.105 Adenosine 5'‑triphosphate (ATP) acts as both a competitive antagonist and allosteric modulator at NMDA receptor channels. At low concentrations of glutamate, ATP inhibits currents through NMDA receptor channels, but has a potentiating effect at saturating glutamate concentrations.106

Modulation of NMDA Receptor Channels Via The Lipid Bilayer Lipids are the major building blocks of cell membranes and participate in signal transduction across biological membranes via interaction with membrane proteins such as ion channels. Brain lipids consist of three major categories: cholesterol, sphingolipids (sphingomyelin, cerebrosides, sulfatides, gangliosides) and glycerophospholipids (phosphatidylcholine, phosphatidylethanolamine, phosphatidylinositols). Numerous reports demonstrate that the activity of many ion channels can be dramatically modulated by lipid molecules such as polyanionic phospholipid PIP2 and a signal transduction lipid, arachidonic acid.107 For example, the activity of several mammalian ion channels is modulated by polyunsaturated fatty acids including arachidonic acid and membrane phospholipids.108‑112 The lipid bilayer and protein‑lipid interaction are critical for mechanosensitive gating and modulation of neuronal K2P channels such as TREK‑1 and TRAAK.111,113,114 Several transient receptor potential (TRPs) channels can be activated by polymodal means such as membrane stretch, osmotic forces, heat and exogenous lipids.115‑118 Stretch‑activated calcium‑dependent K+ channels (SAKCa) are activated by both membrane stretch and amphipathic molecules which insert preferentially into one leaflet of the bilayer.119 Arachidonic acid was shown to potentiate NMDA receptor responses in cerebellar granule cells.108 Although direct binding to a site on the NMDA receptor complex has been indicated, arachidonic acid could also act by altering the receptor lipid environment. Such an effect may be explained in terms of the tension induced by incorporation of asymmetrical, cone‑shaped lipophilic molecules into lipid bilayers and thus creating a mechanical stress on mechanosensitive channels.120,121 Indeed, it was subsequently reported that NMDA receptor responses can be modulated by mechanical stimuli evoked by changes in hydrostatic and osmotic pressure.122 In nucleated patches of mouse central neurons, both hypo‑osmotic solution and positive hydrostatic pressure potentiated NMDA receptor‑mediated currents but not kainate, glycine, or GABA responses, whereas hyper‑osmotic solution and negative pressure had the opposite effect. The effects of mechanical deformation of the plasma membrane on the NMDA receptor response could be mimicked by two classes of amphipathic compounds, arachidonic acid and lysophospholipids. Lysophospholipids inhibited NMDA‑mediated responses whereas arachidonic acid potentiated NMDA receptor currents. Thus the effect of compounds with large hydrophilic heads resembles that of membrane compression, whereas compounds with small hydrophilic heads mimic the effect of membrane stretch.109 This further www.landesbioscience.com

suggests that the membrane tension and/or curvature are important modulators of the NMDA receptor function. Interestingly, in an animal model of stretch‑induced cell injury, Mg2+ block of the NMDA receptor channel was significantly reduced.123 Recently, it has been demonstrated that in the liposome system, stretching of the lipid bilayer, as well as the application of arachidonic acid, alleviate Mg2+ block and potentiate currents through recombinant NMDA receptor channels (Fig. 3).124 This effect can be explained in terms of the bilayer tension induced by mechanical membrane deformation or asymmetrical incorporation of lipid compounds of different charge and/or geometry into the lipid bilayer.120,121 Fatty acids are major components in the mammalian brain condensed in the phospholipids of cellular membranes and are liberated by cellular phospholipases. Thus, any physiological or pathological processes that involve liberation of these fatty acids from neuronal membranes could play an important role in modulating the activity of receptor channels, which are able to sense changes in biophysical properties of the lipid bilayer. Arachidonic acid and decosahexanoic acid (DHA) potentiate NMDA receptor currents in pyramidal neurons of rat cerebral cortex by acting directly on the receptor and not via phospholipase A2, because inhibitors of cyclo‑oxygenase and lipo‑oxygenase do not affect the potentiation.125 Several studies suggest that a positive feedback mechanism may exist between activation of glutamate receptors and release of fatty acids from neuronal cells via activation of phospholipase A2.126,127 Insertion of fatty acids into membrane phospholipids of neighboring neurons may influence membrane fluidity, which could further affect functional properties of integral proteins128 including ion channel complexes. NMDA receptor channels are coupled to large multi‑protein membrane complexes, which further act as mediators of NMDA receptor signaling. Carboxyl‑termini of NR1 and NR2 subunits are tethered to the postsynaptic density protein network (PSD) via the PDZ domains of the membrane associated guanylate kinase protein family members such as PSD‑95, PSD‑93, and SAP102.129‑131 These proteins were reported to regulate synaptic plasticity, long term potentiation and learning processes as well as pain transmission associated with NMDA receptor signaling.132,133 Additionally, several structural proteins of the postsynaptic density network, including the neuronal intermediate filament, myosin regulatory light chain and actin cytoskeletal proteins, were also shown to interact with NMDA receptor subunits presumably stabilizing NMDA receptor‑PSD complexes.134‑136 Another component of postsynaptic densities, spectrin, was found to interact with the C‑terminal domains of NR1 and NR2 subunits and presumably links these receptors to the actin cytoskeleton.137 Indeed the activity of NMDA receptor channels depends on the integrity of actin.138,139 Interestingly, NMDA receptor‑mediated long term potentiation and depression are associated with changes in spine morphology driven by modulation of actin dynamics.140,141 Recently, a novel PIP2 mediated interaction of NMDA receptor channels with a‑actinin has been described. Tethering of NMDA receptor C‑termini to the plasma membrane PIP2 favours channel opening whereas PIP2 hydrolysis significantly reduces NMDA receptor‑mediated currents.142 Furthermore, NMDA receptor mediated long term depression was found to be associated with phospholipase C‑induced hydrolysis of PIP2 and loss of dendritic spines due to depolarization of spine actin.143 Thus structural modifications of the NMDA receptor‑actin linkage and/or formation and shrinkage of dendritic spines associated with

Channels

339


Figure 3. Modulation of Mg2+ block by stretch and arachidonic acid. (A) Stretch response of NMDA receptor channels. Representative currents were recorded from a liposome patch containing reconstituted recombinant NR1a and NR2A receptor subunits in response to external application of agonists glutamate and glycine. (B) Potentiation of NMDA receptor currents by arachidonic acid in liposome membrane patches. The I‑V curve for NR1a + NR2A subunit combinations was obtained in the presence of 5 mM arachidonic acid evoked by voltage ramps from ‑100 mV to +100 mV. (C) A schematic diagram of polymodal modulation of NMDA receptor currents. At the glutamatergic synapse, coincidental release of glutamate and membrane depolarization and/or membrane stretch releases the resting Mg2+ block leading to ionic influx (Adapted from Kloda et al.124).

synaptic plasticity may also account for the mechanosensitive gating of NMDA receptor channels during synaptic transmission. Mg2+ block confers on the NMDA receptor the capacity to act as a molecular coincidence detector and is an important factor in synaptic transmission. Thus, a physiological consequence of the effect of fatty acids on the Mg2+ block of NMDA receptors would 340

be its enhancement of LTP. Indeed, there is evidence that DHA is crucial for induction of LTP and the inhibition of phospholipase A2 (to block arachidonic acid release) prevents induction of LTP in the hippocampal CA1 region.144 Interestingly, the dietary intake of DHA enhanced the learning ability and improved spatial cognition of rodents145,146 further indicating the importance of fatty acids in learning and memory. In addition to fatty acids, there is evidence that lipid rafts can also modulate the function of NMDA receptor channels.52 Lipid rafts are membrane microdomains which are enriched with cholesterol and sphingolipids. These microdomains play an important role in cellular signaling processes.147‑149 NMDA receptor channels have been shown to be associated with lipid rafts150,151 which have been found to play a critical role in the maintenance and function of synapses.152 Depletion of plasma membrane cholesterol plays a critical role in NMDA‑receptor mediated Ca2+ influx in hippocampal cultured neurons and has a dramatic effect on neuronal excitability.153 The exact mechanism of how lipid raft micro‑domains influence neuronal excitability and NMDA receptor sensitivity and function is unclear. Alteration of neurotransmitter affinity by lipid raft components has been reported for ionotropic receptors154,155 and specific raft lipid‑protein interactions have been proposed to influence the agonist affinity of several receptor channels.156 Although functional regulation of NMDA receptor channels appears to be associated with complex molecular systems including neuregulins, or protein kinases and phospholipases, other aspects of the lipid environment could play a significant role in this process. Lipid rafts could affect the function of NMDA receptor channels directly via changes in the biophysical properties of the lipid bilayer, which can occur during “raft” recruitment, as well as via distinct lipid composition. For example, the biophysical properties of NMDA receptor channels could depend on the different lipid types present in lipid rafts, such as cholesterol and sphingolipids, as well as heparan sulfate proteoglycans (HSPG). The latter is another component of the lipid rafts which has been shown to mediate and regulate NMDA receptor activity as well as promoting LTP and stabilization of synapses during early synaptogenesis.157 The HSPG can bind neurotoxic amyloid‑b‑peptide which is one of the characteristic hallmarks of Alzheimer’s disease.158 Such binding may affect the fluidity and/or curvature of plasma membrane leading to over‑activation of NMDA receptor channels and excitotoxicity.

Concluding Remarks In recent years there has been considerable progress in discovery of NMDA receptor‑specific ligands, which has enabled structure-function analysis and significantly advanced knowledge about the role of these important ion channels during synaptic transmission. Several of these ligands have been used in clinical trials for disorders associated with glutamate‑mediated excitoxicity and pain. Modulation of NMDA receptors via the lipid environment offers further potential for development of a novel physiological rationale, not only for treatment, but also for prevention of neurodegenerative disorders that target NMDA receptor channels. These may include the use of naturally occurring amphipathic molecules such as polyunsaturated fatty acids (PUFAs) (components of fish oil) in clinical trials and promotion of healthy diet. Future studies designed to refine a relationship between different NMDA receptor channels and their

Channels



ligands and structural aspects of NMDA receptor complexes will advance our understanding of the role of NMDA receptor signaling in the central nervous system. References 1. Bliss TV, Collingridge GL. A synaptic model of memory: Long term potentiation in the hippocampus. Nature 1993; 361:31‑9. 2. Castellano C, Cestari V, Ciamei A. NMDA receptors in learning and memory processes. Curr Drug Targets 2001; 2:273‑83. 3. Cull‑Candy S, Brickley S, Farrant M. NMDA receptor subunits: Diversity, development and disease. Curr Opin Neurobiol 2001; 11:327‑35. 4. Mayer ML, Westbrook GL, Guthrie PB. Voltage dependent block by Mg2+ of NMDA responses in spinal cord neurons. Nature 1984; 309:261‑3. 5. Nowak L, Bregestovsky P, Ascher P, Herbet A, Prochiantz A. Magnesium gates glutamate‑activated channels in mouse central neurons. Nature 1984; 307:462‑5. 6. Waxman EA, Lynch DR. N‑methyl‑D‑aspartate receptor subtypes: Multiple roles in excitoxicity and neurological disease. Neuroscientist 2005; 11:37‑49. 7. Rosi S, Ramirez‑Amaya V, Hauss‑Wegrzyniak B, Wenk G. Chronic brain inflammation leads to a decline in hippocampal NMDA‑R1 receptors. J Neuroinflammation 2004; 1:12. 8. Fan MMY, Raymon LA. N‑methyl‑D‑aspartate (NMDA) receptor function and excitotoxicity in Huntington’s disease. Prog Neurobiol 2007; 81:272‑93. 9. Kew JNC. Positive and negative allosteric modulation of metabotropic glutamate receptors: Emerging therapeutic potential. Pharmacol Ther 2004; 104:233‑44. 10. Kristiansen LV, Huerta I, Beneyto M, Meador‑Woodruff JH. NMDA receptors and schizophrenia. Curr Opin Pharmacol 2007; 7:48‑55. 11. Tsai G, Coyle JT. Glutamatergic mechanisms in schizophrenia. Annu Rev Pharmacol Toxicol 2002; 42:165‑79. 12. Ballard TM, Pauly‑Evers M, Higgins GA, Ouagazzal AM, Mutel V, Borroni E, Kemp JA, Bluethmann H, Kew JN. Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug‑resistant nonhabituating hyperactivity. J Neurosci 2002; 22:6713‑23. 13. Liao D, Hessler NA, Malinov R. Activation of postsynaptically silent synapses during pairing‑induced LTP in CA1 region of hippocampal slice. Nature 1995; 375:4000‑4. 14. Durand GM, Kovalchuk Y, Konnerth A. Long‑term potentiation and functional synapse induction in developing hippocampus. Nature 1996; 381:71‑5. 15. Isaac JT, Crair MC, Nicoll RA, Malenka RC. Silent synapses during development of thalamocortical inputs. Neuron 1997; 18:269‑80. 16. Lin SY, Constantine‑Paton M. Suppression of sprouting: An early function of NMDA receptors in the absence of AMPA/kainite receptor activity. J Neurosci 1998; 18:3725‑37. 17. Albensi BC, Ilkanich E. Open‑channel blockers of the NMDA receptor complex. Drug News Perspect 2004; 17:557‑62. 18. Dingledine R, Borges K, Bowie D, Traynelis SF. The glutamate receptor ion channels. Pharmacol Rev 1999; 51:7‑61. 19. Kohr G. NMDA receptor function: Subunit composition versus spatial distribution. Cell Tissue Res 2006; 326:439‑46. 20. Paoletti P, Neyton J. NMDA receptor subunits: Function and pharmacology. Curr Opin Pharmacol 2007; 7:39‑47. 21. Laube B, Kuhse J, Betz H. Evidence for a tetrameric structure of recombinant NMDA receptors. J Neurosci 1998; 18:2954‑61. 22. Sasaki YF, Rothe T, Premkumar LS, Das S, Cui J, Talantova MV, Wong HK, Gong X, Chan SF, Zhang D. Characterization and comparison of the NR3A subunit of the NMDA receptor in recombinant system and primary cortical neurons. J Neurophysiol 2002; 87:2052‑63. 23. Perez‑Otano I, Schulteis CT, Contractor A, Lipton SA, Trimmer JS, Sucher NJ, Heinemann SF. Assembly with the NR1 subunit is required for surface expression of NR3A‑containing NMDA receptors. J Neurosci 2001; 21:1228‑37. 24. Matsuda K, Fletcher M, Kamiya Y, Yuzaki M. Specific assembly with the NMDA receptor 3B subunit controls surface expression and calcium permeability of NMDA receptors. J Neurosci 2003; 5:10064‑73. 25. Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 2002; 415:793‑8. 26. Monyer H, Burnashew N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression of the rat brain and functional properties of four NMDA receptors. Neuron 1994; 12:529‑40. 27. Akazawa C, Shigemoto R, Bessho Y, Nakanishi S, Mizuno N. Differential expression of five N‑methyl‑D‑aspartate receptor subunit mRNAs in the cerebellum of developing and adult rats. J Comp Neurol 1994; 347:150‑60. 28. Lynch DR, Guttmann RP. NMDA receptor pharmacology: Perspectives from molecular biology. Curr Drug Targets 2001; 2:215‑31. 29. Petralia RS, Yokotani N, Wenthold RJ. Light and electron microscope distribution of the NMDA receptor subunit NMDAR1 in the rat nervous system using a selective anti‑peptide antibody. J Neurosci 1994; 14:667‑96.


30. Rigby M, Le Bourdelles B, Heavens RP, Kelly S, Smith D, Butler A, Hammans R, Hills R, Xuereb JH, Hill RG, Whiting PJ, Sirinathsinghji DJS. The messenger RNAs for the N‑methyl‑D‑aspartate receptor subunits show region‑specific expression of different subunit composition in the human brain. Neuroscience 1996; 73:429‑447. 31. Scherzer CR, Landwehrmeyer GB, Kerner JA, Counihan TJ, Kosinski CM, Standaert DG, Daggett LP, Velicelibi G, Penney JB, Young AB. Expression of N‑methyl‑D‑aspartate receptor subunit mRNAs in the human brain: Hippocampus and cortex. J Comp Neurol 1998; 390:75‑90. 32. Wenzel A, Fritschy JM, Mohler H, Benke D. NMDA receptor heterogeneity during postnatal development of the rat brain: Different expression of the NR2A, NR2B and NR2C subunit proteins. J Neurochem 1997; 68:469‑478. 33. Monyer H, Sprengel R, Schoepfer R, Herb A, Higuchi M, Lomeli H, Burnashev N, Sakmann B, Seeburg PH. Heteromeric NMDA receptors: Molecular and functional distinction of subtypes. Science; 1992; 22:1217‑21. 34. Quinlan EM, Philpot BD, Huganir RL, Bear MF. Rapid experience‑dependent expression of synaptic NMDA receptors in visual cortex in vivo. Nat Neurosci 1999; 2:352‑7. 35. Dunah AW, Yasuda RP, Wang YH, Luo J, Dávila‑García M, Gbadegesin M, Vicini S, Wolfe BB. Regional and ontogenic expression of the NMDA receptor subunit NR2D protein in rat brain using a subunit‑specific antibody. J Neurochem 1996; 67:2335‑45. 36. Standaert DG, Landwehrmeyer GB, Kerner JA, Penney Jr JB, Young AB. Expression of NMDAR2D glutamate receptor subunit mRNA in neurochemically identified interneurons in the rat neostriatum, neocortex and hippocampus. Brain Res Mol Brain Res 1996; 42:89‑102. 37. Del Valle‑Pinero AY, Suckow SK, Zhou Q, Perez FM, Verne GN, Caudle RM. Expression of the N‑methyl‑D‑aspartate receptor NR1 splice variants and NR2 subunit subtypes in the rat colon. Neuroscience 2007; 147:164‑73. 38. Ciabarra AM, Sullivan JM, Gahn LG, Pecht G, Heinemann S, Sevarino KA. Cloning and characterization of c‑1: A developmentally regulated member of a novel class of the ionotropic glutamate receptor family. J Neurosci 1995; 15:6498‑508. 39. Nishi M, Hinds H, Lu HP, Kawata M, Hayashi Y. Motoneuron‑specific expression of NR3B, a novel NMDA‑type glutamate receptor subunit that works in a dominant‑negative manner. J Neurosci 2001; 21:RC185. 40. Vicini S, Wang JF, Li JH, Zhu WJ, Wang YH, Luo JH, Wolfe BB, Grayson DR. Functional and pharmacological differences between recombinant N‑methyl‑D‑aspartate receptors. J Neurophysiol 1998; 79:555‑66. 41. Mishizen‑Eberz AJ, Rissman RA, Carter TL, Ikonomovic MD, Wolfe BB, Armstrong DM. Biochemical and molecular studies of NMDA receptor subunits NR1/2A/2B in hippocampal subregions throughout progression of Alzheimer’s disease pathology. Neurobiol Dis 2004; 15:80‑92. 42. Wenthold RJ, Prybylowski K, Standley S, Sans N, Petralia RS. Trafficking of NMDA receptors. Annu Rev Pharmacol Toxicol 2003; 43:335‑58. 43. Standley S, Roche KW, McCallum J, Sans N, Wenthold RJ. PDZ domain suspension of an ER retention signal in NMDA receptor NR1 splice variants. Neuron 2000; 28:887‑96. 44. Scott DB, Blanpied TA, Swanson GT, Zhang C, Ehlers MD. An NMDA receptor ER retention signal regulated by phosphorylation and alternative splicing. J Neurosci 2001; 21:3063‑72. 45. Sans N, Prybylowski K, Petralia RS, Chang K, Wang YX, Racca C, Vicini S, Wenthold RJ. NMDA receptor trafficking through an interaction between PDZ proteins and the exocyst complex. Nat Cell Biol 2003; 5:520‑30. 46. Wang YT, Yu XM, Salter MW. Ca2+‑independent reduction of N‑methyl‑D‑aspartate channel activity by protein tyrosine phosphatase. Proc Natl Acad Sci USA 1996; 93:1721‑5. 47. Roche KW, Standley S, McCallum J, Dune Ly C, Ehlers MD, Wenthold RJ. Molecular determinants of NMDA receptor internalization. Nat Neurosci 2001; 4:794‑802. 48. Yu XM, Askalan R, Keil GJ, Salter MW. NMDA channel regulation by channel‑associated protein tyrosine kinase Src. Science 1997; 275:674‑8. 49. Pelkey KA, Askalan R, Paul S, Kalia LV, Nguyen TH, Pitcher GM, Salter MW, Lombroso PJ. Tyrosine phosphatase STEP is a tonic brake on induction of long‑term potentiation. Neuron 2002; 34:127‑38. 50. Prybylowski K, Wenthold RJ. N‑Methyl‑D‑aspartate receptors: Subunit assembly and trafficking to the synapse. J Biol Chem 2004; 279:9673‑6. 51. Salter MW, Kalia LV. SRC Kinases: A hub for MDA receptor regulation. Nat Rev 2004; 5:317‑27. 52. Schrattenholz A, Soskic V. NMDA receptors are not alone: Dynamic regulation of NMDA receptor structure and function by neuregulins and transient cholesterol‑rich membrane domains leads to disease‑specific nuances of glutamate‑signalling. Curr Top Medic Chem 2006; 6:663‑86. 53. Verdoorn RA, Burnashev N, Monyer H, Seeburg PH, Sakmann B. Structural determinants of ion flow through recombinant glutamate receptor channels. Science 1991; 252:1715‑8. 54. Hume RI, Dingledine R, Heinemann SF. Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 1991; 253:1028‑31. 55. Burnashev N, Monyer H, Seeburg PH, Sakmann B. Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 1992; 8:189‑98.

Channels

341

Structure and Function of NMDA Receptor-Channels 56. Wollmuth LP, Kuner T, Sakmann B. Adjacent asparagines in the NR2‑subunit of the NMDA receptor channel control the voltage dependent block by extracellular Mg2+. J Physiol 1998; 506:13‑32. 57. Kupper J, Ascher P, Neyton J. Internal Mg2+ block of recombinant NMDA channels mutated within the selectivity filter and expressed in Xenopus oocytes. J Physiol 1998; 507:1‑12. 58. Wollmuth LP, Kuner T, Seeburg PH, Sakman B. Differential contribution of the NR1‑and NR2A‑subunits to the selectivity filter of recombinant NMDA receptor channels. J Physiol 1996; 491:779‑97. 59. Masuko T, Kashiwagi K, Kuno T, Nguyen ND, Pakh AJ, Fukuchi J, Igarashi K, Williams KA. Regulatory domain (R1‑R2) in the amino terminus of the N‑methyl‑D‑aspartate receptor, effects of spermine, protons, and ifenprodil and structural similarity to bacterial leucine/isoleucin/valine binding protein. Mol Pharmacol 1999; 55:957‑69. 60. Paoletti P, Perin‑Dureau F, Fayyazuddin A, Le Goff A, Callebaut I, Neyton J. Molecular organization of a zinc binding N‑terminal modulatory domain in NMDA receptor subunit. Neuron 2000; 28:911‑25. 61. Meddows E, Le Bourdelles B, Grimwood S, Wafford K, Sandhu S, Whiting P, Mcllhinney RA. Identification of molecular determinants that are important in the assembly of N‑methyl‑D‑aspartate receptors. J Biol Chem 2001; 276:18795‑803. 62. McIlhinney RAJ, Philipps E, Le Bourdelles B, Grimwood S, Wafford K, Sandhu S, Whiting P. Assembly of N‑methyl‑D‑aspartate (NMDA) receptors. Biochem Soc Trans 2003; 31:865‑8. 63. Stern‑Bach Y, Bettler B, Hartley M, Sheppard PO, O‘Hara PJ, Heinemann SF. Agonist selectivity of glutamate receptors is specified by two domains structurally related to bacterial amino acid binding proteins. Neuron 1994; 13:1345‑57. 64. Furukawa H, Gouaux E. Mechanisms of activation, inhibition and specificity: Crystal structures of the NMDA receptor NR1 ligand‑binding core. EMBO J 2003; 22:2873‑85. 65. Furukawa H, Singh SK, Mancusso R, Gouaux E. Subunit arrangements and function in NMDA receptors. Nature 2005; 438:185‑92. 66. Yao Y, Mayer ML. Characterization of a soluble ligand binding domain of the NMDA receptor regulatory subunit NR3A. J Neurosci 2006; 26:4559‑66. 67. Mayer ML, Olson R, Gouaux E. Mechanisms of ligand binding to GluR0 ion channels: Crystal structures of the glutamate and serine complexes and a closed apo state. J Mol Biol 2001; 311:815‑36. 68. Mayer ML. Glutamate receptors at atomic resolution. Nature 2006; 440:456‑62. 69. Palmer GC. Neuro protection by NMDA receptor antagonists in a variety of neuropathologies. Curr Drug Targets 2001; 2:241‑71. 70. Mothet JP. Physiological relevance of endogenous free D‑serine in the mammalian brain: Are scientists on a royal road for the treatment of glutamatergic‑related brain disorders? Pathol Biol (Paris) 2001; 49:655‑9. 71. Priestley T, Kemp JA. Kinetic study of the interactions between the glutamate and glycine recognition sites on the N‑methyl‑D‑aspartic acid receptor complex. Mol Pharmacol 1994; 46:1191‑6. 72. Kew JNC, Kemp JA. Ionotropic and metabotropic glutamate receptor structure and pharmacology. Psychopharmacol 2005; 179:4‑29. 73. Kemp JA, Leeson P. The glycine site of the NMDA receptor‑five years on. TIPS 1993; 14:20‑5. 74. Kemp JA, McKernan RM. NMDA receptor pathways as drug targets. Nat Neurosci 2002; 5:1039‑42. 75. Auberson YP, Allgeier H, Bischoff S, Lingenhoehl K, Moretti R, Schmutz M. 5‑Phosphono methylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A rather than 1A/2B receptor composition. Bioorg Med Chem Lett 2002; 12:1099‑102. 76. Chaperon F, Muller W, Auberson YP, Tricklebank MD, Neijt HC. Substitution for PCP, disruption of prepulse inhibition and hyperactivity induced by N‑methyl‑D‑aspartate receptor antagonists: Preferential involvement of the NR2B rather than NR2A subunit. Behav Pharmacol 2003; 14:477‑87. 77. Feng B, Tse HW, Skifter DA, Morley R, Jane DE, Monaghan DT. Structure-activity analysis of a novel NR2C/NR2D‑preferring NMDA receptor antagonist: 1‑(phenanthrene‑2carbonyl) piperazine‑2,3‑dicarboxylic acid. Br J Pharmacol 2004; 141:508‑16. 78. Harty TP, Rogawski MA. Felbamate block of recombinant N‑methyl‑D‑aspartate receptors: Selectivity for the NR2B subunit. Epilepsy Res 2000; 39:47‑55. 79. Donevan SD, McCabe RT. Conantokin G is an NR2B‑selective competitive antagonist of N‑methyl‑D‑aspartate receptors. Mol Pharmacol 2000; 58:614‑23. 80. Ragnarsson L, Yasuda T, Lewis RJ, Dodd PR, Adams DJ. NMDA receptor subunit‑dependent modulation by conantokin‑G and Ala(7)‑conantokin‑G. J Neurochem 2006; 96:283‑91. 81. Baskaya MK, Rao AM, Donaldson D, Prasad MR, Dempsey RJ. Protective effects of ifenprodil on ischemic injury size, blood‑brain barrier breakdown and edema formation in focal cerebral ischemia. Neurosurgery 1997; 40:364‑70. 82. Williams K. Ifenprodil, a novel NMDA receptor antagonist: Site and mechanism of action. Curr Drug Targets 2001; 2:285‑98. 83. Perin‑Dureau F, Rachline J, Neyton J, Paoletti P. Mapping the binding site of the neuroprotectant ifenprodil on NMDA receptors. J Neurosci 2002; 22:5955‑65.

342

84. Legendre P, Westbrook GL. The inhibition of single N‑methyl‑D‑aspartate‑activated channels by zinc ions in cultured rat neurons. J Physiol 1990; 429:429‑49. 85. Christine CW, Choi DW. Effect of zinc on NMDA receptor‑mediated channel currents in cortical neurons. J Neurosci 1990; 10:108‑16. 86. Parsons CG. NMDA receptors as targets for drug action in neuropathic pain. Eur J Pharmacol 2001; 429:71‑8. 87. Wu HQ, Rassoulpour A, Goodman JH, Scharfman HF, Bertram EH, Schwarcz R. Kynurenate and 7‑chlorokynurenate formation in chronically epileptic rats. Epilepsia 2005; 46:1010‑6. 88. Bristow LJ, Hutson PH, Kulagowski JJ, Leeson PD, Matheson S, Murray F, Rathbone D, Saywell KL, Thorn L, Watt AP, Tricklebank MD. Anticonvulsant and behavioral profile of L‑701, 324, a potent orally active antagonist at the glycine modulatory site on the N‑methyl‑D‑aspartate receptor complex. J Pharmacol Exp Ther 1996; 279:492‑501. 89. Zhou ZL, Kher SM, Cai SX, Whittemore ER, Espitia SA, Hawkinson JE, Tran M, Woodward RM, Weber E, Keana JF. Synthesis and SAR of novel di‑and trisubstituted 1,4‑dihydroquinoxaline‑2,3‑diones related to licostinel (Acea 1021) as NMDA/glycine site antagonists. Bioorg Med Chem 2003; 11:1769‑80. 90. Ohtani K, Tanaka H, Yoneda Y, Yasuda H, Ito A, Nagata R, Nakamura M. In vitro and in vivo antagonistic activities of SM‑31900 for the NMDA receptor glycine‑binding site. Brain Res 2002; 944:165‑73. 91. Holter SM, Tzschentke TM, Schmidt WJ. Effects of amphetamine, morphine and dizocilpine (MK‑801) on spontaneous alteration in the 8‑arm radial maze. Behav Brain Res 1996; 81:53‑9. 92. Anis NA, Berry SC, Burton NR, Lodge D. The dissociative anesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurons by N‑methyl‑D‑aspartate. Br J Pharmacol 1983; 79:565‑75. 93. Wong EH, Kemp JA, Priestley T, Knight AR, Woodruff GN, Iversen LL. The anticonvulsant MK‑801 is a potent N‑methyl‑D‑aspartate antagonist. Proc Natl Acad Sci USA 1986; 83:7104‑8. 94. Perras C. Memantine for treatment of moderate to severe Alzheimer’s disease. Issues Emerg Health Technol 2005; 64:1‑4. 95. Kemp JA, McKernan RM. NMDA receptor pathways as drug targets. Nat Neurosci 2002; 5:1039‑42. 96. Planells‑Cases R, Montoliu C, Humet M, Fernandez AM, Garcia‑Martinez C, Valera E, Merino JM, Perez‑Paya E, Messeguer A, Felipo V, Ferrer‑Montiel A. A novel N‑methyl‑D‑aspartate receptor open channel blocker with in vivo neuroprotectant activity. J Pharmacol Exp Ther 2002; 302:163‑73. 97. MacLean JN, Schmidt BJ. Voltage‑sensitivity of motoneuron NMDA receptor channels is modulated by serotonin in the neonatal rat spinal cord. J Neurophysiol 2001; 86:1131‑8. 98. Kloda A, Adams DJ. Voltage‑dependent inhibition of recombinant NMDA receptor‑mediated currents by 5‑hydroxytryptamine. Br J Pharmacol 2005; 144:323‑30. 99. Kloda A, Adams DJ. Mutations within the selectivity filter of the NMDA receptor channel influence voltage dependent block by 5‑hydroxytryptamine. Br J Pharmacol 2006; 149:163‑9. 100. Ransom RW, Steck NL. Cooperative modulation of [3H]MK‑801 binding to the N‑methyl‑D‑aspartate receptor ion channel complex by L‑glutamine, glycine and polyamines. J Neurochem 1988; 51:830‑6. 101. Williams K. Modulation and block of ion channels: A new biology of polyamines. Cell Signal 1997; 9:1‑13. 102. Paoletti P, Neyton J, Ascher P. Glycine‑independent and subunit‑specific potentiation of NMDA responses by extracellular Mg2+. Neuron 1995; 15:1109‑20. 103. Masuko T, Kuno T, Kashiwagi K, Kusama T, Williams K, Igarashi K. Stimulatory and inhibitory properties of aminoglycoside antibiotics at N‑methyl‑D‑aspartate receptors. J Pharmacol Exp Ther 1999; 290:1026‑1033. 104. Harvey SC, Skolnick P. Polyamine‑like actions of aminoglycosides at recombinant N‑methyl‑D‑aspartate receptors. J Pharmacol Exp Ther 1999; 291:285‑91. 105. Malayev A, Gibbs TT, Farb DH. Inhibition of the NMDA response by pregnenolone sulphate reveals subtype selective modulation of NMDA receptors by sulphated steroids. Br J Pharmacol 2002; 135:901‑9. 106. Kloda A, Clements JD, Lewis RJ, Adams DJ. Adenosine triphosphate acts as both a competitive antagonist and a positive allosteric modulator at recombinant NMDA receptors. Mol Pharmacol 2004; 65:1386‑96. 107. Hilgemann DW. Oily barbarians breach ion channel gates. Science 2004; 304:223‑4. 108. Miller B, Sarantis M, Traynelis SF, Attwell D. Potentiation of NMDA receptor currents by arachidonic acid. Nature 1992; 355:722‑5. 109. Casado M, Ascher P. Opposite modulation of NMDA receptors by lysophospholipids and arachidonic acid: Common features with mechanosensitivity. J Physiol 1998; 513:317‑30. 110. Patel A, Lazdunski M, Honoré E. Lipid and mechano‑gated 2P domain K+ channels. Curr Opin Cell Biol 2001; 13:422‑8. 111. Maingret F, Fosset M, Lesage F, Lazdunski M, Honoré E. TRAAK is a mammalian neuronal mechano‑gated K+ channel. J Biol Chem 1999; 274:1381‑7. 112. Chemin J, Patel AJ, Duprat F, Lauritzen I, Lazdunski M, Honore E. A phospholipids sensor controls mechanogating of the K+ channel TREK‑1. EMBO J 2005; 24:44‑53.

Channels


Structure and Function of NMDA Receptor-Channels 113. Patel AJ, Honoré E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M. A mammalian two pore domain mechano‑gated S‑like K+ channel. EMBO J 17:4283‑90. 114. Honoré E, Patel AJ, Chemin J, Suchyna T, Sachs F. Desensitization of mechano‑gated K2P channels. PNAS 2006; 103:6859‑64. 115. Maroto R, Raso A, Wood TG, Kurosky A, Martinac B, Hamill OP. TRPC1 forms the stretch‑activated cation channel in vertebrate cells. Nat Cell Biol 2005; 7:179‑85. 116. Minke B, Cook B. TRP channel proteins and signal transduction. Physiol Revs 2002; 82:429‑72. 117. Clapham DE. TRP channels as cellular sensors. Nature 2003; 426:517‑522. 118. Ramsey IS, Delling M, Clapham DE. An introduction to TRP channels. Annu Rev Physiol 2006; 68:619‑47. 119. Qi Z, Chi S, Su S, Naruse K, Sokabe M. Activation of a mechanosensitive BK channel by membrane stress created with amphipaths. Mol Membr Biol 2005; 22:519‑27. 120. Martinac B, Adler J, Kung C. Mechanosensitive ion channels of E. coli activated by amphipaths. Nature 1990; 348:261‑3. 121. Perozo E, Kloda A, Cortes DM, Martinac B. Physical principles underlying the transduction of bilayer deformation forces during mechanosensitive channel gating. Nat Struct Biol 2002; 9:696‑703. 122. Paoletti P, Ascher P. Mechanosensitivity of NMDA receptors in cultured mouse central neurons. Neuron 1994; 13:645‑55. 123. Zhang L, Rzigalinski BA, Ellis EF, Satin LS. Reduction of voltage‑dependent Mg2+ blockade of NMDA current in mechanically injured neurons. Science 1996; 274:1921‑3. 124. Kloda A, Lua L, Hall R, Adams DJ, Martinac B. Liposome reconstitution and modulation of recombinant N‑methyl‑D‑aspartate receptor channels by membrane stretch. PNAS 2007; 104:1540‑5. 125. Nishikawa M, Kimura S, Akaike N. Facilitatory effect of decosahexaenoic acid on N‑methyl‑D‑aspartate response in pyramidal neurons of rat cerebral cortex. J Physiol 1994; 475:83‑93. 126. Dumuis A, Pin JP, Oomagari K, Sebben M, Bockaert J. Arachidonic acid released from striatal neurones by joint stimulation of ionotropic and metabotropic quisqualate receptors. Nature 1990; 347:182‑4. 127. Dumuis A, Sebben M, Fagni L, Prezeau L, Manzoni O, Cragoe EJ, Bockaert J. Stimulation by glutamate receptors of arachidonic acid release depends on the Na2+/Ca2+ exchanger in neuronal cells. Mol Pharmacol 1993; 43:976‑81. 128. Stubbs CD, Smith AD. The modification of mammalian membrane polyunsaturated fatty acid composition in relation to membrane fluidity and function. Biochim Biophys Acta 1984; 779:89‑137. 129. van Zundert B, Yoshii A, Constantine‑Paton M. Receptor compartmentalization and trafficking at glutamate synapses: A developmental proposal. Trends Neurosci 2004; 27:428‑37. 130. Aoki C, Miko I, Oviedo H, Mikeladze‑Dvali T, Alexandre L, Sweeney N, Bredt DS. Electron microscopic immunocytochemical detection of PSD‑95, PSD‑93, SAP‑102 and SAP‑97 at postsynaptic, presynaptic and non synaptic sites of adult and neonatal rat visual cortex. Synapse 2001; 40:239‑57. 131. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunit and the postsynaptic density protein PSD‑95. Science 1995; 269:1737‑40. 132. Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsey MF, Morris RG, Morrison JH, O’Dell TJ, Grants SG. Enhanced long‑term potentiation and impaired learning in mice with mutant postsynaptic density‑95 protein. Nature 1998; 396:433‑9. 133. Tao YX, Rumbaugh G, Wang GD, Petralia RS, Zhao C, Kauner FW, Tao F, Zhuo M, Wenthold RJ, Raja SN. Impaired NMDA‑receptor mediated postsynaptic function and blunted NMDA receptor‑dependent persistent pain in mice lacking postsynaptic density‑93 protein. J Neurosci 2003; 23:6703‑12. 134. Ehlers MD, Fung ET, O’Brien RJ, Huganir RL. Splice variant‑specific interaction of the NMDA receptor subunit NR1 with neuronal intermediate filaments. J Neurosci 1998; 18:720‑30. 135. Amparan D, Avram D, Thomas CG, Lindahl MG, Yang J, Bajaj G, Ishmael JE. Direct interaction of myosin regulatory light chain with the NMDA receptor. J Neurochem 2005; 92:349‑61. 136. Wyszynski M, Lin J, Rao A, Nigh E, Beggs AH, Craig AM, Sheng M. Competitive binding of alpha‑actinin and calmodulin to the NMDA receptor. Nature 1997; 385:439‑42. 137. Wechsler A, Teichberg VI. Brain spectrin binding to the NMDA receptor is regulated by phosphorylation, calcium and calmodulin. EMBO J 1998; 17:3931‑9. 138. Rosemund C, Westbrook GL. Calcium induced actin depolarization reduces NMDA channel activity. Neuron 1993; 10:805‑14. 139. Rosemund C, Westbrook GL. Rundown of N‑methyl‑D‑aspartate channels during whole‑cell recording in rat hippocampal neurons‑role of Ca2+ and ATP. J Physiol (London) 1993; 470:705‑29. 140. Matsuzaki M, Honkura N, Ellis‑Davies GC, Kasai H. Structural basis of long‑term potentiation in single dendritic spines. Nature 2004; 429:761‑6. 141. Zhou Q, Homma KJ, Poo MM. Shrinkage of dendritic spines associated with long term depression of hippocampal synapses. Neuron 2004; 44:749‑57.


142. Michailidis IE, Helton TD, Petrou VI, Mirshahi T, Ehlers MD, Logothetis DE. Phosph atidylinosiotol‑4,5‑Bisphosphate regulates NMDA receptor activity through a‑actinin. J Neurosci 2007; 27:5523‑32. 143. Horne EA, Dell’Acqua M. Phospholipase C is required for changes in postsynaptic structure and function associated with NMDA receptor‑dependent long‑term depression. J Neurosci 2007; 27:3523‑34. 144. Fujita S, Ikegaya Y, Nishikawa M, Nishiyama N, Matsuki N. Docosahexaenoic acid improves long‑term potentiation attenuated by phospholipase A2 inhibitor in rat hippocampal slices. Br J Pharmacol 2001; 132:1417‑22. 145. Tanabe Y, Hashimoto M, Sugioka K, Maruyama M, Fujii Y, Hagiwara R, Hara T, Hossain SM, Shido O. Improvement of spatial cognition with dietary docosahexaenoic acid is associated with an increase in Fos expression in rat CA1 hippocampus. Clin Exp Pharmacol Physiol 2004; 31:700‑3. 146. Gamoh S, Hashimoto M, Sugioka K, Shahdat HM, Hata N, Misawa Y, Masumura S. Chronic administration of docosahexaenoic acid improves reference memory‑related learning ability in young rats. Neuroscience 1999; 93:237‑41. 147. Ikonen E. Roles of lipid rafts in membrane transport. Curr Opin Cell Biol 2001; 13:470‑7. 148. Simons K, Toomre D. Lipid rafts and signal transduction. Nat Rev Mol Cell Biol 2000; 1:31‑9. 149. Brown DA, London E. Function of lipid rafts in biological membranes. Annu Rev Cell Dev Biol 1998; 14:111‑36. 150. Besshoh S, Bawa D, Teves L, Wallace MC, Gurd JW. Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post‑synaptic densities following transient global ischemia in the rat brain. J Neurochem 2005; 93:186‑94. 151. Besshoh S, Chen S, Brown IR, Gurd JW. Developmental changes in the association of NMDA receptors with lipid rafts. J Neurosci Res 2007; 85:1876‑83. 152. Hering H, Lin CC, Sheng M. Lipid rafts in the maintenance of synapses, dendritic spines, and surface AMPA receptor stability. J Neurosci 2003; 23:3262‑71. 153. Frank C, Giammarioli AM, Pepponi R, Fiorentini C, Rufini S. Cholesterol perturbing agents inhibit NMDA‑dependent calcium influx in rat hippocampal primary culture. FEBS Letters 2004; 566:25‑9. 154. Sooksawate T, Simmonds MA. Effects of membrane cholesterol on the sensitivity of the GABA A receptor in acutely dissociated rat hippocampal neurons. Neuropharmacology 2001; 40:178‑84. 155. Burger K, Gimpi G, Fahrenholz F. Regulation of receptor function by cholesterol. Cell Mol Life Sci 2000; 57:1577‑92. 156. Allen JA, Halverson‑Tamboli RA, Rasenick MM. Lipid raft microdomains and neurotransmitter signalling. Nat Rev Naurosci 2007; 8:128‑40. 157. Dityatev A, Dityateva G, Sytnyk V, Delling M, Toni N, Nikonenko I, Muller D, Schachner M. Polysialylated neuronal adhesion molecule promotes remodeling and formation of hippocampal synapse. J Neurosci 2004; 24:9372‑82. 158. Verdler Y, Zarandi M, Penke B. Amyloid b‑peptide interactions with neuronal and glial cell plasma membrane: Binding sites and implications for Alzheimer’s disease. J Pept Sci 2004; 10:229‑48.

Channels

343