Molecular Basis for Differential Inhibition of Glutamate Transporter Subtypes by Zinc Ions

Vandenberg, Robert J.; Mitrovic, Ann D.; Johnston, Graham A.R.

doi:10.1124/mol.54.1.189

Cited by 97 publications

(57 citation statements)

References 37 publications

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“…Zinc also can activate signal transduction pathways, such as protein kinase C, which can promote ROS generation (68,69). Zinc also can augment glutamate-induced neuronal injury by directly inhibiting GABA A channels and inhibiting glutamate re-uptake by blocking excitatory amino acid transporters (EAAT-1) expressed on glial cells (70)(71)(72). During ischemia, activation of Ca-A/K receptor channels, acidosis, and elevated zinc levels can also work synergistically to promote glial injury (73).…”

Section: Resultsmentioning

confidence: 99%

The Role of Zinc in Cerebral Ischemia

Galasso

Dyck

2007

Mol Med

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Ischemic stroke is one of the most pervasive life-threatening neurological conditions for which there currently exists limited therapeutic intervention beyond prevention. As calcium-focused neuroprotective strategies have met with limited clinical success, it is imperative that alternative therapeutic targets be considered in the attempt to antagonize ischemic-mediated injury. As such, zinc, which is able to function both as a signaling mediator and neurotoxin, has been implicated in cerebral ischemia. While zinc was first purported to have a role in cerebral ischemia nearly twenty years ago, our understanding of how zinc mediates ischemic injury is still in its relative infancy. Within this review, we examine some of the studies by which zinc has exerted either neuroprotective or neurotoxic effects during global and focal cerebral ischemia.

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Section: Resultsmentioning

confidence: 99%

The Role of Zinc in Cerebral Ischemia

Galasso

Dyck

2007

Mol Med

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“…53 The second transmembrane domain (TM2) in the aminoterminal half of the EAAT is separate, at least in primary structure, from the glutamate translocation region and is also close to TM3 where Zn 2+ binds to the transporter. 49,54 The TM2 has positive charges at the extra-and intracellular edge and contains a number of polar residues that are highly conserved between the transporter subtypes. Our laboratory has demonstrated that mutations of polar and charged residues within TM2 of EAAT1 to aliphatic residues of similar size and shape selectively alter anion permeability without changing the rate of glutamate transport.…”

Section: Chloride Permeation Pathway Of Eaat1mentioning

confidence: 99%

A channel in a transporter

Ryan

Vandenberg

2005

Clin Exp Pharma Physio

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SUMMARY1. Glutamate transporters (or excitatory amino acid transporters (EAAT)) are responsible for removing synaptically released glutamate from the extracellular space. The failure of EAAT to carry out this role will lead to excessive stimulation of glutamatergic receptors, causing excitotoxicity and cell death.2. Glutamate is cotransported into the cell with three Na + and one H + , followed by the counter-transport of one K + . In addition, glutamate and Na + binding activates an uncoupled chloride conductance. Thus, glutamate transporters can function as both a transporter and an ion channel. At present, there is no clear understanding of the structural basis for the dual functions of glutamate transporters and, in the present review, we shall discuss some recent studies that have started to address this question.3. It is possible to modulate one function of glutamate transporters without affecting the other, which suggests that the two functions have separate molecular determinants, and a number of models have been suggested to account for the dual functions of the EAAT that predict both single and dual pores for transporter function.4. It appears that the two functions of glutamate transporters arise from separate transmembrane domains. The C-terminal region of the transporters forms the glutamate translocation domain, whereas the second transmembrane domain in the N-terminal half of the protein plays a crucial role in chloride channel function. Although the two functions arise from separate molecular determinants, the two functional domains are likely to be in close proximity. The significance of these observations will be discussed in terms of likely functional models for the transport and channel processes.

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“…The different transporters of this family share similar structural traits and exhibit different yet comparable functions. Recent studies in several laboratories have provided significant advances in the understanding of the structure and function of these transporters (13,(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). These findings constitute a new direction in our knowledge of ion coupling, stoichiometry, membrane protein structure, and pathophysiological implications of transporters.…”

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confidence: 99%

Amyotrophic Lateral Sclerosis-linked Glutamate Transporter Mutant Has Impaired Glutamate Clearance Capacity

Trotti¹,

Akiyama²,

Pasinelli³

et al. 2001

Journal of Biological Chemistry

159

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We have investigated the functional impact of a naturally occurring mutation of the human glutamate transporter GLT1 (EAAT2), which had been detected in a patient with sporadic amyotrophic lateral sclerosis. The mutation involves a substitution of the putative N-linked glycosylation site asparagine 206 by a serine residue (N206S) and results in reduced glycosylation of the transporter and decreased uptake activity. Electrophysiological analysis of N206S revealed a pronounced reduction in transport rate compared with wild-type, but there was no alteration in the apparent affinities for glutamate and sodium. In addition, no change in the sensitivity for the specific transport inhibitor dihydrokainate was observed. However, the decreased rate of transport was associated with a reduction of the N206S transporter in the plasma membrane. Under ionic conditions, which favor the reverse operation mode of the transporter, N206S exhibited an increased reverse transport capacity. Furthermore, if coexpressed in the same cell, N206S manifested a dominant negative effect on the wild-type GLT1 activity, whereas it did not affect wild-type EAAC1. These findings provide evidence for a role of the N-linked glycosylation in both cellular trafficking and transport function. The resulting alteration in glutamate clearance capacity likely contributes to excitotoxicity that participates in motor neuron degeneration in amyotrophic lateral sclerosis.

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Molecular Basis for Differential Inhibition of Glutamate Transporter Subtypes by Zinc Ions

Cited by 97 publications

References 37 publications

The Role of Zinc in Cerebral Ischemia

The Role of Zinc in Cerebral Ischemia

A channel in a transporter

Amyotrophic Lateral Sclerosis-linked Glutamate Transporter Mutant Has Impaired Glutamate Clearance Capacity

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