Review
Glutamate signalling in non-neuronal tissues

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Abstract

Since the discovery of its role in the CNS, glutamate, together with its involvement in signalling at synapses, has been the subject of a vast amount of research. More recently, it has become clear that glutamate signalling is also functional in non-neuronal tissues and occurs in sites as diverse as bone, pancreas and skin. These findings raise the possibility that glutamate acts as a more widespread ‘cytokine’ and is able to influence cellular activity in a range of tissue types. The impact of these discoveries is significant because they offer a rapid way to advance the development of therapeutics. Agents developed for use in neuroscience applications might be beneficial in the modulation of pathology peripherally, impacting on conditions such as osteoporosis, diabetes and wound healing.

Section snippets

Glutamate signalling in the CNS

It is beyond the scope of this review to explain in detail the functioning of a glutamatergic synapse 1., 2., 3., 4.. However, the relevance of the discoveries related to glutamate signalling in non-neuronal tissues is dependent on some understanding of the process as it functions in the CNS. Glutamate is the major excitatory neurotransmitter in the CNS and is responsible for most fast synaptic neurotransmission. Among the functions that are dependent on glutamate signalling in the CNS are

Glutamate signalling in non-neuronal sites

Even within the CNS, there is evidence of non-neuronal glutamate signalling activity. Astrocytes, which play prominent roles in EAAT-mediated glutamate recycling, also express functional glutamate receptors 10, and functional NMDA, AMPA and metabotropic receptors have been identified on cerebral endothelial cells 11. In retrospect, clear indications of sites where glutamate signalling could occur outside of the CNS were the result of studies of the distribution of radiolabelled glutamate

Concluding remarks

Clearly, many components of glutamatergic synapses are expressed in several tissues that are remote both functionally and embryologically from the CNS (Table 1). However, it is not yet known whether all the other elements of a synapse are present in these tissues. It seems unlikely that non-neuronal tissues express all the components of a complex central synapse, although the significance of this is unclear. Opponents of the view that glutamate is a more ubiquitous signalling molecule than

Acknowledgements

We would like to thank Dr Nicky Peet for assistance with the preparation of the figures in this article.

Glossary

MK801 (dizocilpine)
(5r,10s)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine hydrogen

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