Glutamate is the main excitatory amino acid neurotransmitter in the brain, and glial cells, like neurones, express a wide variety of ionotropic and metabotropic glutamate receptors (Figure 5.3).
Figure 5.3 Types of glutamate receptors; two fundamentally different classes of glutamate receptors are represented by ionotropic receptors (iGluR) and seven-transmembrane-domain G-protein coupled metabotropic receptors (mGluR).
The iGluR are divided into three distinct subtypes, following the discovery of specific pharmacological tools: AMPA (a -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), kainate (KA) and NMDA (N-methyl-D-aspartate) receptors. Every subtype of ionotropic glutamate receptor is assembled from four to five specific subunits, which determines receptor functional properties. The AMPA and KA receptors are predominantly permeable to Na+ and K+, although they may have Ca2+ permeability (maximal PCa/PNa for AMPA/KA receptors is < 1); NMDA receptors are highly Ca2+ permeable (PCa/PNa ~ 10 — 11). When activated by glutamate, AMPA receptors undergo rapid desensitization (with time constant ~100 ms); KA receptors desensitize slower, and NMDA receptors show almost no desensitization (approximate kinetics of ion current responses to glutamate are shown on the lower panel).
The mGluR mediated intracellular second messenger signalling cascades represented by the InsP3/DAG cascade (mGluRs of Group I, linked to PLC) and cAMP cascade (mGluRs of Groups II and III, linked to AC). The subunits that form the different mGluR are indicated
Ionotropic glutamate receptors (iGluRs) are abundantly expressed in astroglial cells throughout the CNS. Classically, the iGluRs are subdivided into three major classes, different in molecular structure, pharmacology and biophysical properties. The first class is represented by AMPA-type receptors, so called because they are specifically activated by a-amino-3-hydroxy-5-methyl-y-isoxazolepropionate (AMPA). The AMPA receptors are assembled from four subunits, GluRl to GluR4, which form cation channels permeable to Na+ and K+. When the GluR2 subunit is missing from the assembly, the cation channel is also permeable to Ca2+ ions. Glutamate rapidly opens the AMPA receptors, and in the presence of agonist they undergo swift desensitization - i.e. membrane responses mediated through AMPA receptors are fast and are fully inactivated within ~100 ms. AMPA-receptors are present in astroglial cells in most of the brain regions, such as cortex, hippocampus, cerebellum and retina. AMPA receptors are also expressed in astrocytes from corpus callosum and spinal cord and in subpopulations of microglial cells. OPCs and oligodendrocytes express functional AMPA receptors made up predominantly of GluR3 and 4, which mediate Ca2+ influx; there is evidence that a developmental increase in GluR2 expression confers low Ca2+ permeability of AMPA receptors in mature oligodendrocytes, but this issue is hotly debated. NG2-glia expresses functional AMPA receptors in the adult CNS, and they are activated by neuronal activity and can mediate Ca2+ influx.
Kainate (KA)-receptors are specifically activated by kainate and are assembled from GluR5-7, and KA1 and KA2 subunits. Like AMPA receptors, KA receptors are nonselective cation channels permeable to Na+ and K+ and, to a much lesser extent, Ca2+. Responses mediated through KA receptors are generally slower and of longer duration than those mediated by the AMPA subtype. Expression of GluR5-7 and KA1 and KA2 subunits has been detected in astrocytes and oligodendrocytes; physiological studies, however, have not yet detected functional KA receptors in glia. KA receptors have also been identified in microglial cells, but their role remains enigmatic.
NMDA-receptors - the third type of ionotropic glutamate receptors are specifically activated by N-methyl-D-aspartate (NMDA), and are assembled from several subunits (an NR1 subunit, together with NR2A-NR2D and NR3A-NR3B). NMDA receptors are also cation channels, but differ from other iGluRs in their Ca2+ permeability and kinetics. The NMDA receptors are highly permeable for Ca2+ (permeability ratio Ca2+:Na+ is ~ 11:1), and the membrane responses mediated by NMDA receptors are long lasting. Functional NMDA receptors have been demonstrated in astroglial cells in the cortex and spinal cord, and in Müller glia. Recent studies also indicate that NMDA receptors are localized to the myelin sheaths of oligodendrocytes of the optic nerve, corpus callosum and cerebellar white matter. In contrast to neuronal NMDA receptors, glial ones display a weak Mg2+ block, and therefore can be activated at the resting membrane potential (in neurones, the ion channel of the NMDA receptor is blocked by Mg2+, which is removed only when the neurone is depolarized, as e.g. following activation of AMPA receptors).
Metabotropic glutamate receptors (mGluRs) are typical seven-transmembrane-domain (7TM) receptors, which regulate two distinct intracellular signalling pathways (Figure 5.3). The Group I receptors (mGluR 1 and 5) are positively coupled to phospholipase C, and their activation increases the intracellular concentration of InsP3, which subsequently triggers Ca2+ release from the endoplasmic reticulum (ER) store. The remaining mGluR subtypes, which belong to Group II (mGluR2, mGluR3) and Group III (mGluR4, mGluR6-8) are coupled to adenylate cyclase and regulate intracellular levels of cAMP. Astroglial cells predominantly express mGluRl, mGluR3 and mGluR5 (i.e. Group I and II); hence glutamate triggers glial Ca2+ signals and regulates cAMP-dependent reactions, such as inhibition of K+ currents, swelling, proliferation and regulation of expression of glutamate transporters. The mGluRs are also present in immature oligodendrocytes and in microglial cells.
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