Neuronal high-affinity sodium-dependent glutamate transporters (EAATs): targets for the development of novel therapeutics against neurodegenerative diseases.
L-Glutamate is the major excitatory neurotransmitter in mammalian central nervous system, and excitatory amino acid transporters (EAATs) are essential for terminating synaptic excitation and for maintaining extracellular glutamate concentration below toxic levels. Although the structure of these channel-like proteins has not been yet reported, their membrane topology has been hypothesised based on biochemical and protein sequence analyses. In the case of an inadequate clearance from synaptic cleft and from the extrasynaptic space, glutamate behaves as a potent neurotoxin, and it may be related to several neurodegenerative pathologies including epilepsy, ischemia, amyotrophic lateral sclerosis, and Alzheimer disease. The recent boom of glutamate is demonstrated by the enormous amount of publications dealing with the function of glutamate, with its role on modulation of synaptic transmission throughout the brain, mainly focusing: i). on the structure of its receptors, ii). on molecular biology and pharmacology of Glu transporters, and iii). on the role of glutamate uptake and reversal uptake in several neuropathologies. This review will deal with the recent and most interesting published results on Glu transporters membrane topology, Glu transporters physiopathological role and Glu transporters medicinal chemistry, highlighting the guidelines for the development of potential neuroprotective agents targeting neuronal high-affinity sodium-dependent glutamate transporters.
Campiani
Giuseppe
G
Dipartimento Farmaco Chimico Tecnologico (DFCT), Universita' degli Studi di Siena, via Aldo Moro, 53100 Siena, Italy. campiani@unisi.it.
Fattorusso
Caterina
C
De Angelis
Meri
M
Catalanotti
Bruno
B
Butini
Stefania
S
Fattorusso
Roberto
R
Fiorini
Isabella
I
Nacci
Vito
V
Novellino
Ettore
E
D027322:Amino Acid Transport System X-AG / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D015195:Drug Design; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D015394:Molecular Structure; D019636:Neurodegenerative Diseases / Q000188:drug therapy* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017470:Receptors, Glutamate / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
D027322:Amino Acid Transport System X-AG; D008024:Ligands; D018696:Neuroprotective Agents; D017470:Receptors, Glutamate; D018698:Glutamic Acid; D012964:Sodium