Glutamate transporters: the regulatory proteins for excitatory/excitotoxic glutamate in brain

Excitatory aminoacids (EAAs) are stored in glutamatergic neurons and related into synaptic cleft, where they can activate inotropic or metabotropic receptors. Their action ends due to transport mechanisms performed by EAAT transporters (EAAT1/GLAST, EAAT2/GLT1, EAAT3/EAAC1, and EAAT4 or EAAT5). Glutamate neurotoxicity has been described in several neurodegenerative diseases such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD) and amyotropic lateral sclerosis ALS). Some drugs, such as paclitaxel, are able to increase translation of microRNA and could be possible used as regulatory against glutamate neurotoxicity. Abbreviations: AD: Alzheimer’s disease; ALS: amyotrophic lateral sclerosis; AMPA: α-amino-3-hydroxy-5-methyl-isoxazole-4propionate; Asp: aspartate; CSF: cerebral spinal fluid; EAA: excitatory amino acid; EAAC1 (EAAT3): excitatory amino acid carrier; EAAT: excitatory amino acid transporter; GABA: gamma-aminobutyric acid; GDH: glutamate dehydrogenase; GLAST (EAAT1): glutamate – aspartate transporter; GLT1 (EAAT2): glutamate transporter; iGluR: ionotropic glutamate receptor; KA: kaninic acid; L-Glu: L-glutamate; mGluR: metabotropic glutamate receptor; miR: micro RNA; NMDA: N-methyl-D-aspartate; PD: Parkinson’s disease Introduction Some amino acids act as neurotransmitters in the nervous system, being glutamate and aspartate the common excitatory amino acids and GABA, glycine and taurine the inhibitory ones. Of these amino acids, glutamate and GABA are intimately associated, as their metabolism is associated through glutamic acid decarboxylase (E.C. 4.1.1.15.) (Figure 1). Furthermore, GABA and glutamic acid effects are antagonic and they are related with CO2 fixation (relevant to central ventilation). Glutamic acid metabolism is also related with NH3 detoxification (due to a reduction in α-ketoglutarate and glutamate contents and an increase in glutamine). The efflux of glutamate from brain across the hemato-encephalic barrier is much higher than the influx [1-3], meaning that metabolism of glutamate must play an important role in regulating the brain glutamate levels. Studies on metabolic generation of glutamate/glutamine by using radioactive substrates in brain shows that two pathways are involved. Glucose, glycerol, lactate, pyruvate, α-ketoglutarate and β-hydroxybutyrate seem to be metabolized to glutamate in neurons [4,5], as a low specific radioactivity of glutamine is obtained. In glial cells [6], where higher glutamine synthase is present [7,8], low radiolabelled glutamate and higher glutamine marked are obtained. This is the case of acetate, propionate, butyrate, citrate, leucine, GABA, aspartate and ammonia [9]. In order to decrease glutamic acid in synaptic cleft, excitatory amino acids transporters have an important effect. Therefore, in this paper we present some aspects of these proteins. Glutamatergic neurotransmission The excitatory amino acids (EAAs) are stored in synaptic vesicles in glutamatergic neurons and, upon an action potential, are released via exocytosis into the synaptic cleft where they can activate two different families of receptors: ionotropic (ligand-gated ion channels) and metabotropic (GTP-binding protein coupled) receptors. The ligandgated ion channels are further divided into three families: α-amino3-hydroxy-5-methyl-isoxazole-4-propionate (AMPA), kainate (KA) and N–methyl-D-aspartate (NMDA). While AMPA and kainate receptors mediate rapid depolarizing responses at most synapses in the mammalian central nervous system [10], the NMDA receptor participates in synaptic plasticity and synapse formation [11]. The family of metabotropic receptors consists of at least eight subtypes and are involved in the modulation of synaptic signaling by EAAs and other neurotransmitters [12]. The termination of the EAA action takes place by an uptake mechanism that uses the Na+, K+ and pH gradients as a driving force to translocate the neurotransmitters against their concentration gradients, keeping their concentration below the level that activates their receptors (~1 μM) [13-15] (Figure 2). Excessive activation of EAA receptors contributes to brain injury through a process known as excitotoxicity. Therefore, this transport mechanism is not only important for ensuring accurate synaptic signaling but also for limiting the EAA-mediated excitotoxicity Excitatory amino acid (EAA) transporters Three broad subtypes of EAA transport activities have been Correspondence to: Josep J Centelles, Departament de Bioquimica i Biologia Molecular (Biologia), Facultat de Biologia, Universitat de Barcelona, Avda Diagonal, 643. Edifici Prevosti, planta-2, 08028, Barcelona, Spain, Tel: 934021870; E-mail: josepcentelles@ub.edu Received: January 16, 2016; Accepted: January 27, 2016; Published: January 30, 2016 Centelles JJ (2016) Glutamate transporters: the regulatory proteins for excitatory/excitotoxic glutamate in brain J Transl Sci, 2016 doi: 10.15761/JTS.1000123 Volume 2(1): 92-99 extracellular concentrations of EAAs by reducing the driving force required to transport an EAA into the cytoplasm. The second activity is a chloride-dependent transport which exchanges amino acids identified in brain preparations. One type, which is directly coupled to ATP hydrolysis, introduces glutamate into vesicles for release upon depolarization of the synaptic terminal [16]. It indirectly ensures low Glutamine ADP + Pi Glutamine synthetase (GS) (E.C. 6.3.1.2.) Glutaminase (Gase) (E.C. 3.5.1.2.) NH4 H2O Glutamate GABA Glutamate decarboxylase (GD) (E.C. 4.1.1.15.) Oxalacetate Glutamate dehydrogenase (GDH) (E.C. 1.4.1.2.) Glutamate oxalacetate transaminase (GOT) (E.C. 2.6.1.1.) NH4 + NADH Aspartate α-Ketoglutarate CO2 NH4 + ATP