Commentary Glutamate transporter : an unexpected target for some antibiotics

Glutamate transporter (GT) plays a major role in the mechanisms of glutamate homeostasis. Can this transporter system be a therapeutic target for glutamate-mediated neurological disorders? In January's edition of Nature, Rothstein et al (2005) reports that the most commonly used class of antibiotics (β-lactam antibiotics) such as ceftriaxone promoted the expression of GLT1 and demonstrated a functional role in both in vitro and in vivo models of glutamate neurotocixity. These findings indicate that positive promoters of GT expression may have a unique role in neuroprotection through regulating GT expression. This is also encouraging in search for new pharmacological tools for pain management. Glutamate is the major excitatory amino acid neurotransmitter that plays an important role in many physiological functions. Maintaining a physiological range of extracellular glutamate concentration is key to preventing glutamate over-excitation and neurotoxicity that could occur under a variety of pathological conditions. Regulating extracellular glutamate is primarily carried out by an efficient, high-capacity glutamate transporter (GT) system, because clearance of extracellular glutamate via glutamate metabolism or diffusion is negligible. To date, at least five cell membrane GT proteins have been cloned [2,3]. GT is labeled by a common name 'excitatory amino acid transporter' (e.g., EAAT1). Among cell membrane GT, EAAT1 (GLAST), EAAT2 (GLT1), and EAAT3 (EAAC1) are particularly relevant to the regulation of glutamate uptake in broad CNS regions. EAAC1 is generally considered as a neuronal GT, whereas GLAST and GLT1 are primarily astroglial GT, although both GLAST and GLT1 also have been located in neuronal cells during the developmental stage [2,3]. Glutamate has a dual role both as an excitatory neurotransmitter essential for physiological functions and a neurotoxic mediator contributory to pathological processes. Since the homeostasis of extracellular glutamate concentration is critically regulated by neuronal and glial GT, reduced GT expression and/or function would be expected to increase extracellular glutamate concentration with subsequent excessive activation of glutamate receptors and excitotoxicity. Indeed, a large number of studies have shown the detrimental effects from reduced GT expression and function on the pathogenesis of neurological disorders including brain ischemia, epilepsy, spinal cord injury, amyotrophic lateral sclerosis, AIDS neuropathy, and Alzheimer's disease. Given the well-documented role of the glutamatergic system in the mechanisms of pathological pain, it is not surprising that regulation of GT also has been implicated in the central mechanisms of nociceptive processing, such as that following the hindpaw formalin injection or the application of exogenous NMDA or protaglandins in rats Published: 09 February 2005 Molecular Pain 2005, 1:5 doi:10.1186/1744-8069-1-5 Received: 07 February 2005 Accepted: 09 February 2005 This article is available from: http://www.molecularpain.com/content/1/1/5 © 2005 Mao; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.