Neurochemistry of L-Glutamate Transport in the CNS: A Review of Thirty Years of Progress

Abstract

The review highlights the landmark studies leading from the discovery and initial characterization of the Na+-dependent "high affinity" uptake in the mammalian brain to the cloning of individual transporters and the subsequent expansion of the field into the realm of molecular biology. When the data and hypotheses from 1970's are confronted with the recent developments in the field, we can conclude that the suggestions made nearly thirty years ago were essentially correct: the uptake, mediated by an active transport into neurons and glial cells, serves to control the extracellular concentrations of L-glutamate and prevents the neurotoxicity. The modern techniques of molecular biology may have provided additional data on the nature and location of the transporters but the classical neurochemical approach, using structural analogues of glutamate designed as specific inhibitors or substrates for glutamate transport, has been crucial for the investigations of particular roles that glutamate transport might play in health and disease. Analysis of recent structure/activity data presented in this review has yielded a novel insight into the pharmacological characteristics of L-glutamate transport, suggesting existence of additional heterogeneity in the system, beyond that so far discovered by molecular genetics. More compounds that specifically interact with individual glutamate transporters are urgently needed for more detailed investigations of neurochemical characteristics of glutamatergic transport and its integration into the glutamatergic synapses in the central nervous system. A review with 162 references.

Molecular Pharmacology of the Na+-Dependent Transport of Acidic Amino Acids in the Mammalian Central Nervous System.

“…101) Another conformationallyrestricted glutamate analogue (2S,1ЈS,2ЈR)-2-(carboxycyclopropyl)glycine (L-CCG III 102,103) ) is actually a naturally-occurring substance 104) (Fig. 2, for a review see 13) ). It was found to have a very high affinity and specificity for GluT 105) (for a review see 13) ) and recent studies using NMR analyses have shown that L-CCG III can be very rapidly accumulated by brain slices, even against steep concentration gradients.…”

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The crucial discovery of the excitatory properties of acidic amino acids [2][3][4][5] lead only gradually and with considerable delay, to the formulation of the hypothesis of the synaptic role of L-glutamate in the mammalian central nervous system (CNS) 6-9) (for reviews of early history of amino acid research, see [10][11][12][13] ). It may never be possible to identify any single experimental study after which L-glutamate became unequivocally accepted as the most important excitatory synaptic transmitter in the brain and spinal cord, but, it is certain that the discovery of the "high affinity uptake" accumulating L-glutamate into "synaptosomes" 14,15) (for reviews see 13,16,17) ) was an important step in the development of the concept of the glutamatergic neurotransmission in the CNS.

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“…It may never be possible to identify any single experimental study after which L-glutamate became unequivocally accepted as the most important excitatory synaptic transmitter in the brain and spinal cord, but, it is certain that the discovery of the "high affinity uptake" accumulating L-glutamate into "synaptosomes" 14,15) (for reviews see 13,16,17) ) was an important step in the development of the concept of the glutamatergic neurotransmission in the CNS. As a putative mechanism for the necessary removal and inactivation of extracellular L-glutamate it provided a target for pharmacological studies and helped to establish a neurochemical link between L-glutamate and the mechanisms of synaptic transmission.…”

“…As a putative mechanism for the necessary removal and inactivation of extracellular L-glutamate it provided a target for pharmacological studies and helped to establish a neurochemical link between L-glutamate and the mechanisms of synaptic transmission. 13,18,19) Most of the latter experiments were carried out in vitro using tissue "mini-slices" prepared from the rat cerebral cortex or cat spinal cord (for details of the methodology see 20,21) ). Rather than disrupting the nervous tissue by homogenization, the technique was using what might be called "neurochemical dissection".…”

“…31,32) Eventually, several distinct transporters were cloned and characterised [36][37][38][39][40][41][42] cent reviews and additional references see. 13,16,17,[43][44][45][46] Glutamate transporters cloned initially from rat brain tissue or rabbit gastrointestinal tract were named in a somewhat haphazard manner (GLutamate Transporter, GLT; GLutamate and ASpartate Transporter, GLAST; Excitatory Amino Acid Carrier, EAAC). The designations EAAT1 (Excitatory Amino Acid Transporter 1), EAAT2, EAAT3, etc., follow the systematic nomenclature preferentially used when referring to the transporters cloned from human brain tissue but it should be kept in mind that the glutamate transporters (EAAT's) have now been cloned in several laboratories, from several species and, in addition, a number of splice variants have been identified so that the nomenclature has become somewhat less simple than that shown in Table 1 (for reviews see 16,17,[43][44][45][46] ).…”