Glutamatergic system

Glutamate (GLU, L-glutamate) is the most abundant neurotransmitter in the nervous system, used in >90% of synapses, and linked to other neurotransmitter systems. Glutamate is an excitatory neurotransmitter, while γ-aminobutyric acid (GABA), which is synthesized from glutamate by the enzyme L-glutamic acid decarboxylase, is the main inhibitory neurotransmitter. Glutamate is transported across the blood brain barrier by a high affinity transport system; its concentration in the extracellular space is kept at a low level and tightly controlled in the synapse. Excess concentration of glutamate can induce hyperexcitability, and even excitotoxicity and cell death, in postsynaptic neurons.

Neuropeptide N-acetyl-L-aspartyl-L-glutamate is a substrate of glutamate carboxypeptidase (PSMA); PSMA expression may be involved with glutamate excitotoxicity.

Glutamate receptors

Glutamate receptors are located on the dendrites of postsynaptic neurons, but also on astrocytes, oligodendrocytes, and on endothelial cells. iGluRs are also found in heart in cardiac nerve terminals, ganglia, conducting fibres, and possibly in myocardiocytes; in the pancreas, modulating the secretion of insulin and glucagon; in the kidneys; in lungs; in lymphocytes and platelets; in the skin; in bone osteoclasts and osteoblasts; and in the gastrointestinal tract.

There are two very different glutamate receptor groups, ionotropic and metabotropic glutamate receptors (iGluRs and mGluRs, respectively). Ionotropic glutamate receptors are fast-acting ion channels, which activate when glutamate binds to the receptor, and the flow of ions triggers membrane depolarization in the post-synaptic cell, inducing signal transmission. The actions of G-protein-coupled metabotropic glutamate receptors on the ion channels are indirect and slow, involving a secondary messenger system, gene expression, and protein synthesis; mGluRs may function as enhancers of the excitability of the neuron, or on presynpatic side, as inhibitor of neurotransmitter release.

Ionotropic glutamate receptor channels consist of heterotetrameric or homotetrameric subunits. The subunits are divided into three families, named after the ligand that specifically binds to the subunit type: AMPA, kainic acid (kainate), and NMDA. AMPA subunits include GluA1, GluA2, GluA3, GluA4 (previously GluR1-4); kainate subunits include GluK1 (GluR5), GluK2 (GluR6), GluK3 (GluR7), GluK4 (KA-1), and GluK5 (KA-1); and NMDA subunits include GluN1 (NR1), GluN2A (NR2A), GluN2B (NR2B), GluN2C (NR2C), GluN2D (NR2D), GluN3A (NR3A), and GluN3B (NR3B). NMDA receptors (NMDARs) contain only NMDA subunits, and have different subunit distributions in different brain regions. Activation of neuronal NMDARs may require binding of both glutamate and co-agonist, such as glycine or D-serine, to separate subunits. Actions of glycin are restricted to extrasynaptic sites, while D-serine is the key NMDAR modulator in synapses.

Delta family (δ receptors) can be considered as the fourth iGluR family; these receptors are mainly found in cerebellar Purkinje cells.

There are eight subtypes of metabotropic glutamate receptors, mGluR1-8. mGluR1, mGluR4 and mGluR6-8 increase the [Ca2+] in cytoplasm. mGluR5 activates K+ channels, enabling the release of K+. mGluR2 and mGluR3 inhibit adenylyl cyclase, and decrease [cAMP]. Group 1 receptors (mGluR1 and mGluR5) are located only in postsynaptic neurons. Group 1 receptors (mGluR2 and mGluR3) are located also on presynaptic neurons, possibly suppressing glutamate transmission. Group 3 receptors (mGluR4 and mGluR6-8) are located on presynaptic neurons, inhibiting neurotransmitter release. Presynaptic mGluRs may play a role in anxiety disorders, group 1 receptors in learning and memory problems.

mGluR1 is expressed heterogeneously in the human brain, most predominantly in the cerebellum. PET tracers for this receptor include [18F]FITM (Yamasaki et al., 2012), [11C]ITMM (Sakata et al., 2017) and [18F]MK-1312 (Hostetler et al., 2011).

Several PET tracers for mGluR5 have been developed, including [18F]FPEB (Wong et al., 2013; Sullivan et al., 2013; Park et al., 2015; Leurquin-Sterk et al., 2016), [18F]PSS232 (Müller Herde et al., 2015; Warnock et al., 2018), and [11C]ABP688 (Elmenhorst et al., 2010; DeLorenzo et al., 2011; DuBois et al., 2016; Esterlis et al., 2017). Since the level of mGluR5 in white matter and cerebellum is low, reference region methods can be applied in the analysis.

Glutamate transporters

Glutamate transporters are located on both pre- and postsynaptic neurons, and on astrocytes (astroglia) in the central nervous system (CNS), but are also found in other tissues, including heart and liver.

Excitatory amino acid transporter (EAAT) family of transporters remove glutamate from extracellular spaces into neurons and other cells. In addition to L-glutamate, they also transport L- and D-aspartate. Vesicular glutamate transporter (VGluT) family includes intracellular transporters that move cytoplasmic glutamate into synaptic vesicles. The three vesicular glutamate transporters VGluT1-3 are dependent on the proton gradient between the cytosol and vesicles. Cystine-glutamate antiporter (xCT, xC-) is located in plasma membranes, and several PET tracers have been developed for it. Mitochondria have a distinct glutamate transporter.

There are five subtypes of EAATs, EAAT1-5. In CNS, subtypes EAAT1 and EAAT2 are found mainly on glial cells. EAAT2 is responsible of most of the glutamate reuptake. Glial cells convert glutamate into glutamine, which is taken up by presynaptic neurons, converted back to glutamate, and stored in vesicles. EAAT3 and EAAT4 are expressed only on neurons, and EAAT5 only in the retina.


See also:



References:

Hogan-Cann AD, Anderson CM. Physiological roles of non-neuronal NMDA receptors. Trends Pharmacol Sci. 2016; 37(9): 750-767.

Liu H, Leak RK, Hu X. Neurotransmitter receptors on microglia. Stroke Vasc Neurol. 2016; 1(2): 52-58.

Maechler P. Glutamate pathways of the beta-cell and the control of insulin secretion. Diabetes Res Clin Pract. 2017; 131: 149-153.

Majo VJ, Prabhakaran J, Mann JJ, Kumar JS. PET and SPECT tracers for glutamate receptors. Drug Discov Today 2013; 18(3-4): 173-184.

Ribeiro FM, Vieira LB, Pires RG, Olmo RP, Ferguson SS. Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol Res. 2017; 115: 179-191.



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Created at: 2017-10-03
Updated at: 2018-05-21
Written by: Vesa Oikonen