Biomedical Engineering Reference
In-Depth Information
sites due to the fact that most research has been aimed at lowering Glu activity in relation to the
mechanisms of neurodegenerative diseases mentioned previously.
The Glu receptors are divided into two main classes, the ionotropic and the metabotropic Glu
receptors (iGluRs and mGluRs), both of these covering three different receptor classes. The three
iGlu classes are named by the selective agonists
N
-methyl-d-aspartic acid (NMDA), 2-amino-3-
(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA), and kainic acid (KA) receptors. These
are further subdivided into subtypes, NR1, NR2A-D, NR3A,B for NMDA receptors; GluR1-4 for
AMPA receptors; and GluR5-7, KA1,2 for KA receptors (see phylogenetic tree in Chapter 12.1).
iGluRs are tetrameric in structure forming an ion channel l uxing Na, K, and Ca ions upon opening
leading to depolarization of the cell membrane and excitation of the neurons. The mGluRs modu-
lates the activity of neurons and are G-protein-coupled receptors, also named 7TM receptors as
described in Chapter 12. The mGluRs consists of mGluR1-8 and are divided into Groups I, II, and
III based on pharmacology, signal transduction mechanisms, and amino acid sequences. Group I
consists of mGluR1,5 and stimulates phosholipase C, whereas Group II (mGluR2,3) and Group III
(mGluR4,6-8) inhibits the formation of cyclic AMP.
A number of modulatory sites have been recognized on iGluRs as well as on mGluRs and have
been given substantial attention after the limited success with especially iGluR antagonists for
neuroprotection.
The Glu transporters, excitatory amino acid transporters (EAAT), have been studied exten-
sively in recent years and 2 glial and 3 neuronal subtypes have been characterized; EAAT1,2 and
EAAT3-5, respectively. These have different distributions, EAAT2 is the major transporter for Glu
in the forebrain, EAAT3 is the major neuronal transporter in the brain and spinal cord, EAAT4 in
the cerebellum, and EAAT5 in the retina. EAAT3-5 is located in postsynaptic terminals, but a
splice variant of EAAT2 may be the transport system for presynaptic Glu uptake. Furthermore three
subtypes of Glu transporters exist on synaptic vesicles (VGLUT1-3) with the function of packing
Glu into vesicles for subsequent release from the presynaptic terminal. The enzymatic systems for
metabolism of Glu has only been studied to a limited extent in the context of therapeutic potential
and will not be discussed here.
15.7 IONOTROPIC GLUTAMATE RECEPTOR LIGANDS
The development of selective ligands for the different receptor classes within iGluRs has been going
on for almost three decades and especially within the last decade the search for subtype-selective
ligand has taken speed. Within some areas a vast number of potent and selective agents have been
developed, whereas for other areas there is still an urgent need for good ligands, with the purpose
of characterizing the functions of the respective receptors/subtypes to give an understanding of the
physiological and pathophysiological roles of these. Only a limited number of ligands will be dis-
cussed and one specii c example of a development project will be briel y described.
Extensive knowledge about the structure of the ligand-binding domain of iGluRs have been
obtained during the last decade by a number of x-ray structure determinations. These structures
include the apostructure (ligand-binding domain without a ligand) and structures with Glu, other
agonists, antagonists, partial agonists, and modulatory ligands in a ligand-binding construct of dif-
ferent iGluR subtypes (see also Figures 2.11 and 12.7). The detailed structural information gained
by these structures is used extensively in the design of new ligands for the various GluRs as exem-
plii ed in Section 15.9.
15.7.1 NMDA R
ECEPTOR
L
IGANDS
NMDA receptors include a number of different binding sites, and thus several potential targets
for therapeutic attack. NMDA receptors are unique among ligand-gated ion channels, in that they
require two different agonists for activation, Glu (
15.2
) and glycine (
15.58
), and at the same time
