[Frontiers in Bioscience, d701-718, July 20, 1998]
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EXCITATORY AMINO ACID NEUROTRANSMISSION. PATHWAYS FOR METABOLISM, STORAGE AND REUPTAKE OF GLUTAMATE IN BRAIN

Monica Palmada and Josep Joan Centelles

Departament de Bioquímica i Biologia Molecular, Facultat de Química, Universitat de Barcelona, Martí i Franquès, 1, 08028-Barcelona, Spain

Received 5/7/98 Accepted 5/23/98

3. EXCITATORY AMINO ACIDS RECEPTORS

Excitatory aminoacids (aspartate and glutamate) act through two broad classes of receptors: ion channel-linked ionotropic receptors (iGluR) and metabotropic receptors (mGluR), which are coupled with G-proteins inducing intracellular messenger cascades (12).

There are different types of ionotropic and metabotropic glutamate receptors in both neurones and glial cells. Table I shows a summary of the main characteristics of those receptors. Classification of receptors has been possible due to the different affinity to specific agonists and antagonists. A summary of those molecules are given in figure 2.

Table 1. Glutamate receptors

Receptor

Component

Transmembrane

Regions

G-Proteins

Transduction systems

Agonists potency

NMDAR1

4

--

Open

GLU>NMDA

NMDA

NMDAR2A

4

ionic channels

--

NMDAR2B

4

Na+, Ca++

--

NMDAR2C

4

--

NMDAR2D

4

--

GluR1

4

--

Open

QA>DOM» AMPA>GLU>KA

AMPA

GluR2

4

ionic channels

QA>AMPA>GLU>KA

GluR3

4

Na+, K+ (Ca++)

QA>AMPA>GLU>KA

GluR4

4

QA>AMPA>GLU>KA

GluR5

4

--

Open

DOM>KA>QA» GLU>AMPA

Kainate

GluR6

4

ionic channels

DOM>KA>QA>GLU>AMPA

GluR7

4

Na+, Ca++

DOM>KA>GLU>QA>AMPA

KA1

4

KA>QA>DOM>GLU>AMPA

KA2

4

KA>QA>DOM>GLU>AMPA

mGluR1

7

Gq o Gi/Go

Activates PLC

QA>IBO» GLU>tACPD

Metabotropic

mGluR2

7

Gi/Go

Inhibits AC

GLU» tACPD>IBO>QA

mGluR3

7

Gi/Go

Inhibits AC

GLU» tACPD>IBO>QA

mGluR4

7

Gi/Go

Inhibits AC

AP4>GLU>tACPD (QA inactive)

mGluR5

7

Gq o Gi/Go

Activates PLC

QA>GLU» IBO>tACPD

mGluR6

7

Gi/Go

Inhibits AC

--

Glutamate receptors are classified as ionotropic (NMDA, AMPA and kainate) and metabotropic. Depending on the receptor type they show different transmembrane regions and different affinity for the agonists.



Figure 2. Some of the agonists and antagonists of glutamate receptors. Classification of glutamate receptors is possible due to the effect of some agonists and antagonists. Here it is shown the chemical structures of the most common used.

Glial cells, in particular astrocytes, appear to respond to a great variety of neurotransmitters, including glutamate, hormones and growth factors with activation of metabotropic pathways, which may lead to intracellular pH and/or calcium changes. The distribution of different sets of glutamate receptors in different brain regions may classify neurones and glial cells, and appears to be functionally of some significance, both in normal physiological processes as well as during pathological states. The excitatory neurotransmitter glutamate and its large receptor family is probably the most versatile and complex signaling system in the mammalian brain, and possibly also the most susceptible for pathological disturbances.

3.1. Ionotropic glutamate receptors

Four main subtypes of glutamate-gated channels have been characterized pharmacologically and they have been named according to their preferred agonist, N-methyl-D-aspartate (NMDA), high affinity kainate (KA), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and 2-amino-4-phosphobutyrate (AP4). For each of those agonists, a large diversity of receptors have been described (see table 1).

The most studied receptor is NMDA (13,14), and because of this, glutamate ionotropic receptors are often named as NMDA and non-NMDA. Activation of the ionotropic NMDA and non-NMDA receptors increases transmembrane calcium and sodium fluxes, whereas the metabotropic glutamate receptor activation results in generation of inositol triphosphate and inhibition of adenylate cyclase (15). Nevertheless, metabotropic receptors are also related in phosphorylation of NMDA and non-NMDA receptors.

It seems that glutamate ionotropic receptors, specially NMDA receptors, are related with neurodegenerative diseases, as act when glutamate concentration increases. Thus, a noncompetitive NMDA receptor antagonist (memantine) can be used for the treatment of Alzheimer´s disease (16). It has also been seen that injection of kainate causes selective neuronal degeneration similar to that of Huntington´s disease (17). Evidence from animal models suggests that antagonists of the different glutamate receptors might be beneficial in Parkinson´s disease, Huntington´s chorea and amyotrophic lateral sclerosis but the relevance of these models to the human disease is not clear. However, the identification of numerous receptor subtypes in addition to variabilities of distribution and multiple modulatory sites will provide new solutions to these common neurological disorders.

3.1.1. NMDA receptors

NMDA-type ionotropic receptors have not been demonstrated in glial cells, but only in neurons. Those receptors contain (a) a transmitter binding site, which binds glutamate; (b) a regulatory or coactivator site, which binds glycine, (c) a site within the channel that binds phencyclidine and related compounds, (d) a voltage-dependent Mg2+ binding site , and (e) an inhibitory divalent cation site that binds Zn2+. Glycine greatly enhances the actions of NMDA agonists but has no action by itself. Interaction of phencyclidine and related anesthetics to NMDA receptors reproduce most of the symptoms of schizophrenia. A major advance in the understanding of the NMDA receptor was the demonstration by McDonald and Johnston (18) and Flatman et al. (19) that NMDA-induced responses are voltage-dependent. The agonist-induced currents are greatest at moderately depolarized potentials (-30 to -20 mV) and are reduced at both more hyperpolarized and depolarized potentials. Consequently, NMDA receptor action is suppressed at the normal resting potential. The work of Nowak et al. (20) and Mayer et al. (21) demonstrated that the voltage dependency of the NMDA receptor is attributable to extracellular Mg2+ ions that block the ion channel only at potentials more negative than -20 or -30 mV.

In the central nervous system the N-methyl-D-aspartate (NMDA) receptor channel plays an important role in synaptic plasticity and neuronal development. It has an heteromeric configuration consisting of the epsilon (NR2) subunits, which potentiate the channel activity and modulate the functional properties, and zeta 1 (NR1) subunit, which is essential to form functional NMDA receptors channels (22).

3.1.2. Non-NMDA receptors

AMPA and kainate receptors have been regarded as rather impermeable to divalent cations, in particular to Ca2+ (23), although in certain neurons Ca2+-permeable kainate receptors were observed (24-26). Pharmacological studies indicate that the AMPA and kainate receptors are responsible for the voltage-independent portion of the synaptic response in many neuronal pathways. Kainate receptors could probably have multiple actions, e.g. the opening of a voltage-independent cation channel as well as a modulatory action, possibly via calcium channels.

The finding that L-AP4 can potently block synaptic transmission in these systems yet is ineffective as an antagonist of the other well characterized excitatory amino acid agonists indicate that L-AP4 acts at receptors others than those identified by NMDA, kainate or AMPA. Early studies suggested that the AP4 receptor could be identified in presynaptic membranes as a sodium-independent, chloride-dependent L-glutamate binding site.

3.2. Metabotropic glutamate receptors

The metabotropic glutamate receptors (mGluR) are both functionally and pharmacologically different from the family of the ionotropic receptors. The mGluR is coupled to a G protein(s) and evokes a variety of functions by mediating intracellular signal transduction (27,28). It also differs from known ionotropic receptors in agonists selectivity (28,29) (See table 1 and figure 2).

Seven subtypes of mGluR are known to exist (12) but their roles in synaptic physiology are not very understood. They are classified upon their second messenger as follows: mGluR1 and mGluR5 are associated to inositol phosphate (IP) and to changes in calcium concentration and belong to the Group I. mGluR2 and mGluR3 belong to Group II and mGluR4, mGluR6-mGluR8 are related to Group III. All receptors from Groups II and III inhibit the cAMP production.

Postsynaptic group I mGlu receptors may modulate both AMPA and NMDA receptor mediated currents, probably via phosphorylation of the respective ion channels. Group II/III receptor-activation produce neuroprotective effects. In cerebellar Purkinje cells, application of the mGluR agonist trans-1-aminocyclopentane-1,3-dicarboxylic acid, or the active enantiomer, 1S,3R-ACPD, results in a depolarization associated with an inward current and an elevation of intracellular calcium (30).