Glutamate is the principal excitatory neurotransmitter in brain. Our knowledge of the glutamatergic synapse has advanced enormously in the last 10 years, primarily through application of molecular biological techniques to the study of glutamate receptors and transporters………. Glutamate is the most abundant amino acid in the diet. There is no evidence for brain damage in humans resulting from dietary glutamate……… clinical conditions that may respond to drugs acting on glutamatergic transmission include epilepsy, amnesia, anxiety, hyperalgesia and psychosis.

Although glutamate is a simple molecule, its actions in the limbic system and areas concerning anxiety are complex and widespread. These actions are mediated through different combinations of ionotropic and metabotropic glutamate receptors……… For the treatment of clinical anxiety disorder a more delicate regulation of the glutaminergic system is required…….. Metabotropic glutamate receptor agonists and antagonists are in particular promising in this respect. It can be expected that selective modulators of glutamate activity will be of great clinical significance for the treatment of anxiety disorders.

Brain tissue has a remarkable ability to accumulate glutamate. This ability is due to glutamate transporter proteins present in the plasma membranes of both glial cells and neurons……….. the glutamate transporters appear to have more sophisticated functions in the modulation of neurotransmission……….Further, the glutamate transporters provide glutamate for synthesis of e.g. GABA, glutathione and protein, and for energy production. They also play roles in peripheral organs and tissues (e.g. bone, heart, intestine, kidneys, pancreas and placenta). Glutamate uptake appears to be modulated on virtually all possible levels………. Like glutamate itself, glutamate transporters are somehow involved in almost all aspects of normal and abnormal brain activity.

Glutamate (Glu) is the principal excitatory neurotransmitter in the central nervous system…… The role of glutamate in the pathophysiology of migraine is implicated by data from animal and human studies……… Human studies investigating the role of Glu in migraine pathogenesis measured the levels of Glu in plasma, platelets and cerebrospinal fluid, studied its effect on migraine symptoms and examined the effect of Glu in modulating sensitization. Findings from both the animal and the human studies suggest a link between glutamate and migraine and further suggest that glutamate plays a key role in migraine mechanisms. In the future, efforts should be made to further investigate the role of glutamate in migraine pathogenesis and, subsequently, in migraine treatment.

L-glutamate (Glu) has been thought to be an excitatory amino acid neurotransmitter in the mammalian central nervous system (CNS)……… recent molecular biological analyses including ours give rise to a novel function for Glu as an autocrine and/or paracrine factor in bone comprised of osteoblasts, osteoclasts, and osteocytes, in addition to other peripheral tissues including pancreas, adrenal, and pituitary glands. Emerging evidence suggests that Glu could play a dual role in mechanisms underlying maintenance of cellular homeostasis as an excitatory neurotransmitter in the CNS and as an extracellular signal mediator in peripheral autocrine and/or paracrine tissues. In this review, therefore, we summarized the possible signaling by Glu as an extracellular signal mediator in mechanisms underlying maintenance of cellular homeostasis with a focus on bone tissues.

The view that L-glutamate (Glu) is an excitatory amino acid neurotransmitter in the mammalian central nervous system is prevailing on the basis of successful cloning of a number of genes encoding different signaling molecules……… Emerging evidence suggests that Glu could play a dual role in mechanisms underlying the maintenance of cellular homeostasis as an excitatory neurotransmitter in the central nervous system and as an extracellular signal mediator in peripheral autocrine and/or paracrine tissues. In this review, therefore, we would outline the possible signaling system for Glu to play a role as an extracellular signal mediator in mechanisms underlying maintenance of the cellular homeostasis in bone.

Bone is one of the most frequent sites for metastasis of breast and prostate cancers. Bone metastases are associated with pathologic changes in bone turnover and severe pain. The mechanisms that trigger these effects are not well understood, but it is postulated that tumour cells release factors which interfere with signalling processes critical to bone homeostasis. We have identified that several cancer cell lines known to cause bone disruption in animal models of bone metastasis appear to secrete glutamate into their extracellular environment in vitro. Although these cells also express specific glutamate receptors, the implications of this potentially disruptive chemical signal are discussed in relation to normal glutamate-dependent communication processes in bone and a possible mechanistic connection is made between tumour cell glutamate release and the development of pathological changes in bone turnover.

Although the amino acid glutamate is used as an intercellular signaling molecule for normal bone homeostasis, little is known regarding its possible role in the metabolic disruption characteristic of bone metastasis………. This study demonstrates the expression of multiple glutamate transporters in cancer cell lines of non-central nervous system origin. Furthermore, we identify the molecular mechanism responsible for glutamate export and show that this system can be inhibited pharmacologically. By highlighting that glutamate secretion is a common biological feature of cancer cells, this study suggests that tumor-derived glutamate could interfere with glutamate-dependent intercellular signaling in normal bone. Pharmacological interference with cancer cell glutamate release may be a viable option for limiting host bone response to invading tumor cells in bone metastasis.

Several lines of evidence indicate a role for glutamate in the regulation of gut motility and secretion; however, the receptor subtypes that mediate the effects of this amino acid are still incompletely understood. There has, however, been recent progress in pharmacological characterization of enteric glutamate receptor subtypes. In the past two years, investigators have demonstrated that in addition to ionotropic glutamate receptors, the enteric nervous system contains functional group I metabotropic glutamate receptors that appear to participate in enteric reflexes. This opens up an entirely new arena in which to study the roles of glutamate in gut function and presents potential new target sites for drug development.

Although it is well known that the intestinal tract has a high metabolic rate, the substrates that are used to generate the necessary energy remain poorly established……… Under fed conditions, the quantification of substrate used by the gut is complicated by the fact that potential oxidative precursors are supplied from both the diet and the arterial circulation……… Glutamate was the single largest contributor to intestinal energy generation. The results also suggested that dietary glutamate appeared to be a specific precursor for the biosynthesis of glutathione, arginine and proline by the small intestinal mucosa.

Glutamate is a main constituent of dietary protein and is also consumed in many prepared foods as an additive in the form of monosodium glutamate. Evidence from human and animal studies indicates that glutamate is a major oxidative fuel for the gut and that dietary glutamate is extensively metabolized in first pass by the intestine. Glutamate also is an important precursor for bioactive molecules, including glutathione, and functions as a key neurotransmitter. The dominant role of glutamate as an oxidative fuel may have therapeutic potential for improving function of the infant gut, which exhibits a high rate of epithelial cell turnover………… Glutamate is not considered to be a dietary essential, but recent studies suggest that the level of glutamate in the diet can affect the oxidation of some essential amino acids, namely leucine. Given that substantial oxidation of leucine occurs in the gut, ongoing studies are investigating whether dietary glutamate affects the oxidation of leucine in the intestinal epithelial cells. Our studies also suggest that at high dietary intakes, free glutamate may be absorbed by the stomach as well as the small intestine, thus implicating the gastric mucosa in the metabolism of dietary glutamate. Glutamate is a key excitatory amino acid, and metabolism and neural sensing of dietary glutamate in the developing gastric mucosa, which is poorly developed in premature infants, may play a functional role in gastric emptying.