Glutamate (or GLUTAMIC ACID) is an EXCITATORY AMINO ACID, with two isomeric forms: L- and D-glutamic acid. Glutamic and ASPARTIC ACID are the major excitatory NEUROTRANSMITTERS in the CENTRAL NERVOUS SYSTEM. Analogues of glutamic acid such as QUISQUALIC ACID, IBOTENIC ACID, KAINIC ACID and N-methyl-D-aspartate (NMDA) also exhibit marked potency and specificity in the DEPOLARIZATION of neurons. Alongside its role in neurotransmission, glutamate is also involved in intermediary METABOLISM in neural tissue. It is a building block in the synthesis of PROTEINS and PEPTIDES including glutathione, a precursor for the inhibitory neurotransmitter GABA, and plays a role in the detoxification of ammonia in the brain. The diverse roles of glutamate in the central nervous system have led to doubts about its classification as a true neurotransmitter. However, its mechanisms of regulation and release are appropriate for such classification. Glutamate is released from presynaptic terminals by depolarization in a calcium-dependent manner.
After release, glutamate binds to specific postsynaptic receptors (see GLUTAMATE RECEPTORS) and induces excitation of the postsynaptic membrane. Glutamate transporters pump excess glutamic acid from the extracellular space back into neurons. This reuptake mechanism is important and necessary since glutamate is neurotoxic in high concentrations (see EXCITOTOXINS) and glutamate-containing neurons are capable of firing at high frequencies for long periods of time, leading to accumulation of millimolar concentrations in the SYNAPTIC CLEFT. Some effects of glutamate may be mediated by the novel neurotransmitter nitric oxide: glutamate is a potent stimulator of nitric oxide in the brain and there is evidence that activation of NMDA receptors can regulate nitric oxide neurons. Glutamate has been highlighted as having key roles to play in many normal and pathological brain processes. In the normal brain, it is thought to be critically important for physiological processes related to LEARNING and MEMORY in the HIPPOCAMPUS (see LONG-TERM POTENTIATION), as well as neuroendocrine regulation. It is also thought to play a role in diverse pathophysiological disorders such as HUNTINGTON’S CHOREA, PARKINSON’S DISEASE, ALZHEIMER’S DEMENTIA, AMYOTROPHIC LATERAL SCLEROSIS, EPILEPSY, SCHIZOPHRENIA and STROKE. The importance of these fields means that research is very fast moving, although the roles which glutamate plays are not yet completely understood. One specific research goal is to understand the mechanisms responsible for the massive, uncontrolled release of glutamate in ISCHAEMIA.
