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Revision as of 17:34, 3 May 2013

Background

Memantine, pictured below is an antagonist of N-methyl-D-asparate Receptors (NMDARs), a type of ionotropic glutamate receptor. Such receptors are found primarily on neurons. Memantine is the leading Alzheimer's drug that is used to prevent memory and learning capacity decline. Prescribed doses of memantine allows normal physiological activity of NMDARs but prevents overstimulation. Overstimulation causes a phenomenon called excitotoxicity. Excitotoxicity is when neurons are overstimulated by glutamate and as a result the neuron dies. When groups of cells are subject to excitotoxicity, portions of the brain will die resulting in severe brain damage. The effects of excitotoxicity causes a diminish in synaptic plasticity (explain what this is). The diminish in synaptic plasticity leads to learning inability and memory loss. By preventing overstimlation, Memantine aims to prevent excitotoxicity and the resulting diminish in learning inability and memory loss. Thus, memantine treats the memory loss and learning inability characteristic to Alzheimer's Disease.

NMDAR Structure

NMDARs have two nearly symmetrical , called NR1 and NR2. They consist mainly of alpha helices. Each subunit acts as a distinct functional unit, and they each bind a ligand separately. The subunits interact very neatly with one another, with parts of each subunit interacting with polar portion of the other subunit and nonpolar portions interacting likewise.

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NMDAR Binding Sites

Each NMDAR subunit binds a or an agonist in the center of the subunit. In the case of NMDARs the agonist is often N-methyl-D-asparate. For glutamate receptors in general, glycine or ______ may be the agonist.

The of each subunit that interact with the glycine are ________. See better .

NMDAR Ion Channel

When an ligand binds, the subunit undergoes a conformational change. The conformational changes of the two subunits create a central channel The antagonist will then bind to the core

agonist bind, then conformational change, then ion flux in (show binding spot in receptor) (show channel)

NMDA receptor is heterotetramer of two GluN1 (or NR1) and two GluN2 (or NR2) subunits. Each subunit acts as a distinct functional unit. The extracellular domain contains two globular structures, a modulating domain and a ligand binding domain. NR1 bind co-agonists and NR2 binds glutamate. Agonist binding module links to a membrane domain, which has three transmembrane segments and a re-entrant loop. The membrane domain contributes residues to the channel pore. The cytoplasmic domain contains residues that can be modified by series of protein kinases and phosphatases. The cytoplasmic domain also has residues that interact with scaffolding proteins (Vance, 1-2).

GluA2 Structure

     AMPA IGluRs form homotetramers composed of distal subunit partners and proximal subunits partners. Each subunit includes an extracellular amino terminal domain (ATD) which is responsible for receptor trafficking within the membrane, a ligand-binding domain (LBD) which activates the receptor upon binding glutamate, and a transmembrane domain (TMD) which forms the membrane-spanning ion channel. Also present is a carboxy-terminal domain involved in receptor localization and regulation, although the structure of this domain has not been solved.[2] The structure of AMPA IGluRs or in this case GluA2, is unique in that the symmetry of the receptor changes depending on the domain. The ATD has a local two-fold symmetry, the LBD has a two-fold symmetry, while the TMD has a four-fold symmetry. Here is a morph depicting the differnce between subunit type A and B. This symmetry mismatch has implications for function of the receptor with subunits behaving differently depending upon their orientation despite identical primary sequence.[2] For an excellent analysis, see: Glutamate Receptor Symmetry Analysis

The Amino Terminal Domain

     The ATD is responsible for receptor assembly, trafficking and localization. It has two unique sets of interactions which hold the tetramer together. The first set of interactions is present in each pair of dimers and involves both hydrogen bonding and hydrophobic interactions. The second set, which includes residues Ile 203, Thr 204, Ile 205, and Val 209 on both chains among others, effectively holds the pair of dimers together at an angle that is roughly 24 degrees off of the overall two-fold axis.[2][7]

The Transmembrane Domain

     The TMD has a pore structure that is nearly identical to that of the Potassium Channel. With complete four-fold symmetry, 16 helices form a precise pore through which cations can flow through. In the current, inhibitor bound structure, the M3 helices cross at a highly conserved SYTANLAAF motif, with Thr 617, Ala 621, and Thr 625 occluding the ion permeation pathway.[2] The narrowest part of the channel includes the residues Thr 625, Ala 621, and Thr 617, but does not distinguish between positive cations like in the Potassium Channel. Located next to this narrow region lies Alanine 622, which is replaced with a threonine in the Lurcher mouse model mentioned previously. This mutation, which introduces a much bulkier residue, prevents the helices from closing properly, resulting in a constitutively open ion channel.[2]

The Ligand Binding Domain

     The LBD is located just above the TMD and has an overall two-fold axis of symmetry. Within each LBD lies the so-called “clamshell”. This structure is responsible for binding glutamate and “sensitizing” the receptor to allow passage of cations through the channel. Residues Pro 89, Leu 90, Arg 96, Ser 142, & Glu 193 among others (residue numbers in 1ftj model), which are responsible for tightly binding glutamate within the clamshell, are highly conserved. Glutamate binding causes a conformational change (Alternate View) in the LBD which pulls the M3 helices in the TMD apart, opening the channel and allowing for cation passage. A morph of the conformational change in the LBD upon glutamate binding can be seen here. Uniquely, due to the varied importance of the homotetramer subunits due to symmetry mismatch, the interaction of glutamate with the distal subunits is predicted to result in a greater conformational change. Thus these distal subunits play a more critical role in channel sensitization and activation.[2]