Transporters forL‐glutamate: An update on their molecular pharmacology and pathological involvement

Abstract

L-Glutamate (Glu) is the major excitatory neurotransmitter in the mammalian CNS and five types of high-affinity Glu transporters (EAAT1-5) have been identified. The transporters EAAT1 and EAAT2 in glial cells are responsible for the majority of Glu uptake while neuronal EAATs appear to have specialized roles at particular types of synapses. Dysfunction of EAATs is specifically implicated in the pathology of neurodegenerative conditions such as amyotrophic lateral sclerosis, epilepsy, Huntington's disease, Alzheimer's disease and ischemic stroke injury, and thus treatments that can modulate EAAT function may prove beneficial in these conditions. Recent advances have been made in our understanding of the regulation of EAATs, including their trafficking, splicing and post-translational modification. This article summarises some recent developments that improve our understanding of the roles and regulation of EAATs.

Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: Implications for the role of astrogliosis in amyotrophic lateral sclerosis

“…Although we cannot exclude the possibility of increased synthesis and/or cell surface expression of neuronal EAATs, the greater transport capacity of astrocytic EAATs (Rothstein et al, 1996) suggests the FW-mediated increase in uptake V max may reflect enhanced efficiency of these EAATs. Short-term stimulation of EAAT activity subsequent to AMPA receptor activation could occur by a number of recognized mechanisms (other than genomic) known to regulate astrocytic EAAT activity (Beart and O'Shea, 2007), including the action of Glu (Duan et al, 1999;Ginsberg et al, 1995;Levy et al, 1995;Munir et al, 2000) which is released by injury (Gilman et al, 1994;Pellegrini-Giampietro et al, 1990). As AMPA receptor activation preferentially affects neurons, including motoneurons, this early cellular response to excitotoxicity could be a consequence of neuronal-astrocytic crosstalk (Barbeito et al, 2004).…”

The mGluR2/3 Agonist LY379268 Blocks the Effects of GLT-1 Upregulation on Prepulse Inhibition of the Startle Reflex in Adult Rats

“…For its fundamental role in regulating Glu levels, GLT-1 is involved in the pathophysiology of several neuropsychiatric diseases (Beart and O'Shea, 2007;Lauriat and McInnes, 2007;Sheldon and Robinson, 2007). Some evidence suggests a role for GLT-1 in the pathophysiology of schizophrenia as follows: (1) a susceptibility locus for schizophrenia is probably located within or near the GLT-1 gene (Deng et al, 2004), and this gene is reportedly dysregulated in patients with schizophrenia (Shao and Vawter, 2008); (2) GLT-1 immunoreactivity is increased in the thalamus, striatum, and prefrontal cortex of schizophrenia patients McCullumsmith and Meador-Woodruff, 2002;Smith et al, 2001); (3) the antipsychotic clozapine specifically downregulates GLT-1 expression and function both in vivo and in vitro (Melone et al, 2001(Melone et al, , 2003VallejoIllarramendi et al, 2005); (4) the psychotomimetics PCP specifically upregulates GLT-1 expression and function (Fattorini et al, 2008); and (5) pharmacologically induced GLT-1 upregulation is associated with an impairment of the prepulse inhibition (PPI) of the startle reflex, a neurophysiological parameter altered in schizophrenia patients and in animal models of schizophrenia, in a dihydrokainate (DHK)-reversible manner, and worsens PCP-induced PPI alterations Melone et al, 2009b).…”

Discovery of a Tamoxifen-Related Compound that Suppresses Glial l-Glutamate Transport Activity without Interaction with Estrogen Receptors

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