Glutamate

Glutamate is the most important excitatory transmitter in the central nervous system. Glutamate ensures the mediation and perception of sensory impressions and plays an important role in the control of motor activity. The transmitter is crucial for brain functions such as learning and memory. Glutamate axons that reach and leave the hippocampus are of great importance here.

In terms of taste, glutamate is responsible for the taste quality unami, and is therefore used in the food industry as a flavor enhancer. It is associated with the Chinese restaurant syndrome.

Glutamate synthesis occurs in 2 ways:

• Glutamate arises from the amino acid glutamine (which mostly comes from glial cells) via a glutaminnase.
• The 2nd pathway is from alpha-ketoglutarate (from the citrate cycle of neuronal mitochondria) via an aminotransferase. It is taken up into salivary vesicles via a vesicular glutamate transporter. Glutamate release occurs by exocytosis.

Glutamate receptors: Glutamate exerts its action by binding to and activating cell surface receptors. Four families of glutamate receptors have been identified in mammals:

• AMPA receptors (ionotropic)
• Kainate receptors (ionotropic; they resemble AMPA receptors but are much less abundant).
• NMDA receptors (ionotropic)
• Metabotropic glutamate receptors (mGlur)

In electrophysiology, the subdivision of ionotropic glutamate receptors into:

• NMDA
• and
• nonNMDA receptors.

The group of nonNMDA receptors accordingly includes the AMPA and kainate receptors. Ionotropic receptors activate membrane channels where ions can pass through when open. Metabotropic receptors are G-protein coupled receptors. They exert their action through a complex second messenger system. Many synapses use multiple species of glutamate receptors.

AMPA receptors (AMPA-R - acronym for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) areionotropic receptors. They are specialized for rapid excitation. In many synapses, they generate their stimulatory electrical responses in a fraction of a millisecond after stimulation. Excitation of the postsynaptic membrane by glutamate leads to its depolarization by the AMPA receptors. An excitatory postsynaptic potential (EPSP) is generated. Only high frequency repetitive depolarization (25-200Hz) or simultaneous depolarization through multiple converging coincident synapses leads to charge repulsion of the Mg ion on the NMDA receptor and its opening. This then leads to calcium influx into the postsynapse and increased intracellular Ca concentration.

Kainate receptors are named after the receptor prototype kainate (kainic acid). Kainate receptors are ionotropic receptors with large transmembrane pores that allow Na+, K+, Ca2+, and Cs+ to pass, but are not permeable to anions.

NMDA receptors (N-methyl-D-aspartate receptors - they are named after the selective agonist N-methyl-D-aspartate, which is also effective) are also ionotropic. However, they differ from AMPA receptors in that they are permeable to calcium upon activation. NMDA receptors play a role primarily in neuronal development, synaptic plasticity, and central nervous system pathologies (Monaghan et al. 1989; Dingledine et al. 1999). Their properties make them particularly important in learning and memory.

Metabotropic receptors (mGlu-R) act through second-messenger systems to produce slow, sustained effects on their targets. They exist in large numbers and variety. Metatropic receptors are G-protein coupled receptors. Gq -mediated, they activate phospholipase C (PLC). Gi/o-mediated they inhibit adenylcylcase, activate K+ channels or deactivate neuronal Ca+ channels.

Because of its role in synaptic "plasticity," glutamate is involved in cognitive functions such as learning and memory in the brain. The form of plasticity known as long-term potentiation occurs at glutamatergic synapses in the hippocampus, neocortex, and other parts of the brain. Glutamate acts not only as a point-to-point transmitter, but also by superimposing signals between synapses, in which the sum of the glutamate released from an adjacent synapse produces extrasynaptic signal transmission. In addition, glutamate plays an important role in the regulation of embryonic brain development and synapse formation (synaptogenesis).

Glutamate transporters (Glut T) are found in neuronal and glial membranes. They rapidly remove glutamate from the extracellular space. In brain injury or disease, they often work in reverse, and excess glutamate can accumulate outside the cells. This process causes calcium ions to enter cells through NMDA receptor channels, leading to neuronal damage and eventually cell death. This is called excitotoxicity.

Mechanisms of neuronal apoptosis (excitotoxicity): Ca2⁺ concentration regulates various mitochondrial functions and when increased uncontrollably, the excessive intracellular Ca2⁺ concentration can damage mitochondria. Ca2⁺ concentration increases intracellular nitric oxide (NO) concentration. Excess NO molecules form free radicals, increasing oxidative stress in the cell.

Glutamate or Ca2⁺ mediate the promotion of transcription factors for proapoptotic genes or the downregulation of transcription factors for antiapoptotic genes. Therefore, the net effect of increased Glu / Ca2⁺ concentration is cell apoptosis.

Excitotoxicity due to excessive glutamate release and impaired uptake occurs as part of the ischemic cascade and is associated with stroke, autism, some forms of mental retardation, and diseases such as amyotrophic lateral sclerosis, lathyrism, and Alzheimer's disease .

In contrast, decreased glutamate release is observed in conditions of classic phenylketonuria, resulting in developmental disruption of glutamate receptor expression.

Glutamic acid has been implicated in epileptic seizures. Microinjection of glutamic acid into neurons leads to spontaneous depolarizations at intervals of about one second, and this firing pattern resembles the so-called paroxysmal depolarization shift in epileptic seizures. This change in resting membrane potential at seizure foci could lead to spontaneous opening of voltage-activated calcium channels, resulting in the release of glutamic acid and further depolarization.