Glutamate transporters as drug targets.
The L-glutamate (Glu) has been hypothesized as an excitatory amino acid neurotransmitter in the mammalian central nervous system after successful cloning and identification of a number of genes encoding signaling machineries required for the neurocrine at synapses in the brain. These include excitatory amino acid transporters (EAATs) for signal termination and vesicular Glu transporters (VGLUTs) for signal output through exocytotic release, in addition to Glu receptors (GluRs) for signal input. These Glu signaling molecules not only play key roles in mechanisms associated with synaptic plasticity such as learning and memory, but also participate in the etiology and pathology of different neuropsychiatric disorders and neuronal cell death seen in various neurodegenerative diseases. Of the aforementioned Glu signaling molecules, EAATs are essential for the termination of signal transmission mediated by Glu as well as for the prevention of neurotoxicity mediated by this endogenous excitotoxin, while VGLUTs are crucial for the storage of Glu in synaptic vesicles to suffice for the definition of a glutamatergic phenotype. Many early desperate efforts were devoted to the search and development of novel compounds with a therapeutic window toward GluRs, while relatively little attention was paid to either EAATs or VGLUTs in this aspect. In this review, therefore, we will summarize the classification and functionality of EAATs and VGLUTs with a focus on their possibilities as potential therapeutic targets for different neurodegenerative and neuropsychiatric disorders related to malfunction of Glu signaling in human beings.
Hinoi
Eiichi
E
Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School of Natural Science and Technology, Kanazawa, Ishikawa 920-1192, Japan.
Takarada
Takeshi
T
Tsuchihashi
Yuriko
Y
Yoneda
Yukio
Y
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D027322:Amino Acid Transport System X-AG / Q000187:drug effects / Q000378:metabolism*; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism; D015195:Drug Design; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D026901:Membrane Transport Proteins / Q000187:drug effects* / Q000378:metabolism*; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D022161:Transport Vesicles / Q000187:drug effects / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D026901:Membrane Transport Proteins; D018698:Glutamic Acid