Glutamate transporters

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AD= : Alzheimer disease; ALS= : amyotrophic lateral sclerosis; AQP4= : aquaporin 4; EAAT= : excitatory amino acid transporter; GABA= : γ-aminobutyric acid; PD= : Parkinson disease; SLC= : solute carrier family; SOD1= : superoxide dismutase 1; TNF= : tumor necrosis factor; VGLUT= : vesicular glutamate transporter. Glutamate is the major excitatory neurotransmitter in the mammalian CNS and is critically involved in mechanisms of synaptic plasticity, memory, and neuronal or glial cell death. Glutamate is stored in synaptic vesicles by the action of vesicular glutamate transporters (VGLUTs) and, following its release, exerts its effects via inotropic and metabotropic receptors. The synaptic effects of glutamate are rapidly terminated by action of glutamate transporters (excitatory amino acid transporters [EAATs]) located on the plasma membrane of astrocytes and neurons. These 2 transporter families differ in many of their functional properties. Studies in knockout mice and other experimental models have provided insights into the physiologic role of VGLUTs and EAATs in normal glutamatergic transmission and their potential role in neurologic disorders. Alterations in the function or expression of EAATs have been implicated in the pathophysiology of stroke, epilepsy, amyotrophic lateral sclerosis (ALS), Alzheimer disease (AD), Parkinson disease (PD), Huntington disease, HIV-associated dementia, malignant glioma, and other neurologic disorders. Loss of VGLUT has been reported in PD and AD. The physiology, regulation, and involvement of glutamate transporters in neurologic disease have been the subjects of several excellent reviews.1–10 ### Vesicular glutamate transporters. Glutamate is synthesized in the presynaptic terminals from glutamine by action of phosphate-activated glutaminase and is translocated into the lumen of presynaptic vesicles via VGLUTs3,5,6 (figure). VGLUT isoforms belong to the solute carrier family (SLC) SLC17 type I phosphate transporter family and are highly homologous, consisting of 12 putative transmembrane spanning domains. Glutamate uptake is driven by a proton (H+)-dependent electrochemical gradient across the vesicle membrane created by a vacuolar-type ATPase. Unlike other vesicular neurotransmitter transporters, the driving force for VGLUTs depends predominately on the existence of a vesicular membrane potential gradient, rather than a pH gradient. Figure Distribution and mechanisms of vesicular glutamate transporters (VGLUT) and excitatory amino acid transporters …