Abstract
Glutamate is the most abundant free amino acid in the brain and is at the crossroad between multiple metabolic pathways. Considering this, it was a surprise to discover that glutamate has excitatory effects on nerve cells, and that it can excite cells to their death in a process now referred to as “excitotoxicity”. This effect is due to glutamate receptors present on the surface of brain cells. Powerful uptake systems (glutamate transporters) prevent excessive activation of these receptors by continuously removing glutamate from the extracellular fluid in the brain. Further, the blood–brain barrier shields the brain from glutamate in the blood. The highest concentrations of glutamate are found in synaptic vesicles in nerve terminals from where it can be released by exocytosis. In fact, glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. It took, however, a long time to realize that. The present review provides a brief historical description, gives a short overview of glutamate as a transmitter in the healthy brain, and comments on the so-called glutamate–glutamine cycle. The glutamate transporters responsible for the glutamate removal are described in some detail.
Highlights
Outside the community of biomedical scientists, glutamate is probably best known as ‘‘monosodium glutamate’’ or ‘‘MSG’’ which is the sodium salt of glutamic acid and a white crystalline solid used as a flavor or taste enhancer in food
The present review provides a brief historical description, gives a short overview of glutamate as a transmitter in the healthy brain, and comments on the so-called glutamate–glutamine cycle
Glutamate is continuously being released to the extracellular fluid, and inhibition of glutamate uptake leads to extracellular buildups of glutamate within seconds (Jabaudon et al 1999)
Summary
Outside the community of biomedical scientists, glutamate is probably best known as ‘‘monosodium glutamate’’ or ‘‘MSG’’ which is the sodium salt of glutamic acid and a white crystalline solid used as a flavor or taste enhancer in food (food additive number E620). Because the glutamate receptor proteins are expressed on the surface of the cells in such a way that they can only be activated from the outside, it follows that glutamate exerts its neurotransmitter function from the extracellular fluid. Because there are no enzymes extracellularly that can degrade glutamate, low extracellular concentrations require cellular uptake This uptake is catalyzed by a family of transporter proteins located at the cell surface of both astrocytes and neurons The reason is the high flexibility of the glutamate molecule which permits several conformations that are only minimally less favorable energetically at body temperature than the lowest energy conformation (Bridges et al 1991) This implies that glutamate can take many shapes and explains, in part, why the various glutamate binding proteins (transporters, receptors, enzymes) can have quite different binding sites and still be able to bind glutamate. A large number of compounds are available, and there are a number of excellent reviews on the topic (e.g. BraunerOsborne et al 1997; Jensen and Brauner-Osborne 2004; Shigeri et al 2004; Ritzen et al 2005; Thompson et al 2005; Bridges and Esslinger 2005; Shimamoto 2008; Bridges et al 2012a, b; Gregory et al 2013; Gonda 2012; Bonaccorso et al 2011)
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