Glutamate

Glutamate (neurotransmitter)

Glutamate refers to the anion of glutamic acid in its role as a neurotransmitter.

Glutamate is the most abundant excitatory neurotransmitter in the nervous system.

It is used by every major excitatory function in the brain, accounting in total for well over 90% of the synaptic connections in the human brain.

Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord.

It is also used at most synapses that are capable of increasing or decreasing in strength.

In addition it serves as the primary neurotransmitter for some localized brain regions, such as cerebellum granule cells.

Excessive glutamate release can overstimulate the brain and lead to excitotoxicity causing cell death resulting in seizures or strokes.

Excitotoxicity has been implicated in certain chronic diseases including ischemic stroke, epilepsy, amyotrophic lateral sclerosis, Alzheimer’s disease, Huntington disease, and Parkinson’s disease.

There are three major biochemical receptors for glutamate: AMPA receptors, NMDA receptors, and metabotropic glutamate receptors.

A fourth class, known as Kainate receptors, are similar to AMPA receptors, but much less abundant is a fourth class.

Synapses use a variety of types of glutamate receptors.

AMPA receptors are receptors specialized for fast excitation,producing excitatory electrical responses in their targets a fraction of a millisecond after being stimulated.

NMDA receptors are also ionotropic, but are permeable, when activated, to calcium.

NMDA receptors properties make them important for learning and memory.

It is involved in cognitive functions such as learning and memory in the brain via glutamatergic synapses in the hippocampus, neocortex, and other parts of the brain.

It works not only as a point-to-point transmitter, but through synaptic crosstalk between synapses in which summation of glutamate released from a neighboring synapse creates extrasynaptic signaling.

It sounds plays important roles in the regulation of growth cones and synaptogenesis during brain development.

A major constituent of a wide variety of proteins.

One of the most abundant amino acids in the body.

Usually enough is obtained from the diet that there is no need for any to be synthesized.

It can also be synthesized from alpha-Ketoglutaric acid, which is produced as part of the citric acid cycle by a series of reactions whose starting point is citrate.

It cannot cross the blood-brain barrier unassisted, but it is actively transported into the nervous system by a high affinity transport system, which maintains its concentration in brain fluids at a fairly constant level.

It is synthesized in the CNS from glutamine as part of the glutamate-glutamine cycle by the enzyme glutaminase.

Synthesis 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.

Glutamate exerts its effects by binding to and activating cell surface receptors.

There are four families of glutamate receptors identified, known as AMPA receptors, kainate receptors, NMDA receptors, and metabotropic glutamate receptors.

AMPA receptors, kainate receptors, NMDA receptors are ionotropic, when activated they open membrane channels that allow ions to pass through.

The metabotropic family are G protein-coupled receptors, exerting their effects via a complex second messenger system.

EAAT and VGLUT, are glutamate transporters found in neuronal and glial membranes.

EAAT and VGLUT transporters remove glutamate from the extracellular space.

In brain injury or disease excess glutamate can accumulate outside cells.

The accumulation of excess glutamate causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death.

This process is called excitotoxicity.

Ca2+-concentration regulates mitochondrial functions and excessively high intracellular Ca2+-concentration can damage mitochondria.

Ca2+-concentration increases intracellular nitric oxide (NO) concentration. forming free radicals increasing oxidative stress.

An increased Glu/Ca2+-concentration leads to 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.

Decreased glutamate release is observed with phenylketonuria leading to developmental disruption of glutamate receptor expression.

Glutamic acid has been implicated in epileptic seizures.