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  • br Vesicular glutamate transporters VGLUTs br Conclusions Du

    2021-09-22


    Vesicular glutamate transporters (VGLUTs)
    Conclusions Due to the molecular cloning of EAAT and VGLUT subtypes, a better understanding of the functional properties of these carriers has been elucidated over the last few years. In the case of the EAATs, specific blockers, such as trans-2,4-PDC, dihydrokainic Solamargine and dl-TBOA have been developed to evaluate the physiological role of EAATs. On the other hand, a lack of specific blockers for the VGLUTs has limited progress in clarifying their physiological mechanisms of action. Future development of new regulatory molecules for the EAATs and VGLUTs is expected to accelerate our understanding of the role of these carriers in synaptic transmission, neuropathological conditions and ultimately higher brain function.
    Acknowledgements
    Introduction Glutamatergic synapses are the most prevalent excitatory synapses in the central nervous system (CNS). The glutamate released at the synapses is taken up by neurons and astrocytes via sodium-dependent glutamate transporters, also termed excitatory amino acid transporters (EAATs) (Nicholls and Attwell, 1990, Anderson and Swanson, 2000, Maragakis and Rothstein, 2001, Schousboe, 2003; Fig. 1A). Astrocytes take up the majority of released glutamate, and astrocytic glutamate transport is vital for proper performance of both the mature and the developing CNS (Rothstein et al., 1996, Tanaka et al., 1997, Matsugami et al., 2006, Petr et al., 2015). Up to now, five transporter subtypes (EAAT 1-5) have been identified and cloned from mammalian tissues, with astrocytes mainly expressing EAAT1 and EAAT2 (Danbolt, 2001). The isoforms share Solamargine many common structural and molecular properties; but they differ in functional characteristics such as glutamate transport rates and substrate affinities (Vandenberg and Ryan, 2013, Fahlke et al., 2016). EAAT glutamate uptake is driven by the co-transport of three sodium ions and one proton, as well as the counter-transport of one potassium ion (Fig. 1B). This complex stoichiometry frees up enough energy to permit active transport of glutamate into the cell against a steep concentration gradient. Additionally it ensures that glutamate transport only reverses under extreme conditions (Szatkowski and Attwell, 1994). For various pathological situations, acute or chronic reduction in overall glial glutamate uptake capacity contributes to increased extracellular glutamate concentrations and results in excitotoxicity (Allaman et al., 2011). Glutamate uptake by astrocytes thus not only shapes synaptic transmission by regulating the availability of glutamate to postsynaptic neuronal receptors, but also protects neurons from hyper-excitability and excitotoxic damage. The present review will focus on discussing the molecular and cellular physiology of glial sodium-dependent glutamate transporters, which are mediators of complex interactions and inter-dependence between neurons and astrocytes in the brain.
    Molecular basis of glutamate transport
    Glutamate transporters in astrocytes
    Conclusion
    Conflict of interest
    Acknowledgements
    Introduction
    Glutamate Glu is present in high concentrations in practically all of the brain areas and its receptors are widely distributed and expressed in neuronal and non-neuronal cells. This excitatory amino acid plays an important role in higher brain functions such as cognition, learning and memory formation (Birur et al., 2017, Fonnum, 1984, Headley and Grillner, 1990, Stanley et al., 2017), as well as in other plastic changes involved in the regulation of CNS development like synapse induction and elimination (Durand et al., 1996, Murphy-Royal et al., 2015, Rabacchi et al., 1992), and cell migration and differentiation (Campana et al., 2017, Komuro and Rakic, 1993, Rossi and Slater, 1993, Song et al., 2017). Glu concentration in the synaptic space is in the low micromolar range (3–4 μM) and around 10 μM in the extracellular fluid and in the cerebrospinal fluid (Danbolt, 2001, Hamberger and Nystrom, 1984, Lehmann et al., 1983).