Glutamate is an amino acid and a neurotransmitter (a chemical that nerve cells use to send signals to other cells). It is by a wide margin the most abundant excitatory neurotransmitter in the vertebrate nervous system. It is used by every major excitatory function in the vertebrate brain, estimated to account for 90% of the synaptic connections in the human brain. It also serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells. Biochemical receptors for glutamate fall into two major classes, known as ionotropic glutamate receptors and metabotropic glutamate receptors. The ionotropic glutamate receptors consist of AMPA receptors, NMDA receptors, and kainate receptors. The metabotropic glutamate receptors consist of eight different individual receptors, being split into group I, group II, and group III. Many synapses use multiple types of glutamate receptors. AMPA receptors are ionotropic receptors specialized for fast excitation: in many synapses they produce excitatory electrical responses in their targets a fraction of a millisecond after being stimulated. NMDA receptors are also ionotropic, but they differ from AMPA receptors in being permeable, when activated, to calcium. Their properties make them particularly important for learning and memory. Metabotropic receptors act through second messenger systems to create slow, sustained effects on their targets. 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 takes place at glutamatergic synapses in the hippocampus, neocortex, and other parts of the brain. Glutamate works not only as a point-to-point transmitter, but also through spill-over synaptic crosstalk between synapses in which summation of glutamate released from a neighboring synapse creates extrasynaptic signaling/volume transmission. In addition, glutamate plays important roles in the regulation of growth cones and synaptogenesis during brain development.
Biosynthesis Glutamate is a very major constituent of a wide variety of proteins; consequently it is one of the most abundant amino acids in the human body. Glutamate is formally classified as a non-essential amino acid, because it can be synthesized (in sufficient quantities for health) from α-ketoglutaric acid, which is produced as part of the citric acid cycle by a series of reactions whose starting point is citrate. Glutamate cannot cross the blood–brain barrier unassisted, but it is actively transported out of the nervous system by a high affinity transport system, which maintains its concentration in brain fluids at a fairly constant level. Glutamate is synthesized in the central nervous system from glutamine as part of the glutamate–glutamine cycle by the enzyme glutaminase. This can occur in the presynaptic neuron or in neighboring glial cells. Glutamate itself serves as metabolic precursor for the neurotransmitter GABA, via the action of the enzyme glutamate decarboxylase.
Cellular effects
Glutamate exerts its effects by binding to and activating cell surface receptors. In mammals, four families of glutamate receptors have been identified, known as AMPA receptors, kainate receptors, NMDA receptors, and metabotropic glutamate receptors. The first three families are ionotropic, meaning that when activated they open membrane channels that allow ions to pass through. The metabotropic family are G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system.
Disease, disabilities, and pharmacology Glutamate transporters, EAAT and VGLUT, 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 cells. This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death, and is called excitotoxicity. The mechanisms of cell death include
Ca2+-concentration regulates different mitochondrial functions and upon increasing uncontrollably, the excessively high intracellular Ca2+-concentration can damage mitochondria. Ca2+-concentration increases intracellular nitric oxide (NO) concentration. Excessive NO-molecules form free radicals and thus increase cell's oxidative stress. Glutamate or Ca2+ mediate promotion of transcription factors for pro-apoptotic genes, or downregulation of transcription factors for anti-apoptotic genes. Thus 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 intellectual disability, and diseases such as amyotrophic lateral sclerosis, lathyrism, and Alzheimer's disease. In contrast, decreased glutamate release is observed under conditions of classical phenylketonuria leading to developmental disruption of glutamate receptor expression. Glutamic acid has been implicated in epileptic seizures. Microinjection of glutamic acid into neurons produces spontaneous depolarisations around one second apart, and this firing pattern is similar to what is known as paroxysmal depolarizing shift in epileptic attacks. This change in the resting membrane potential at seizure foci could cause spontaneous opening of voltage-activated calcium channels, leading to glutamic acid release and further depolarization.
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