Charge Compensation Mechanism of a Na+-coupled, Secondary Active Glutamate Transporter

Grewer, Christof; Zhang, Zhou; Mwaura, Juddy; Albers, Thomas; Schwartz, Alexander; Gameiro, Armanda

doi:10.1074/jbc.m112.364059

Cited by 29 publications

(43 citation statements)

References 41 publications

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“…These currents were interpreted as caused by Na + binding to the glutamate-free transporter, or conformational changes associated with this binding, as has been demonstrated for other Na + -coupled, secondary-active transporters [117-118]. Interestingly, transient currents were also observed in the sole presence of K + on both the intracellular and extracellular side of the membrane, indicating that K + binding and/or translocation is/are also electrogenic [72] (Fig. 2B, see Fig.…”

Section: Molecular Transport Mechanismmentioning

confidence: 91%

SLC1 glutamate transporters

Grewer

Gameiro

Rauen

2013

Pflugers Arch - Eur J Physiol

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112

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The plasma membrane transporters for the neurotransmitter glutamate belong to the solute carrier 1 (SLC1) family. They are secondary active transporters, taking up glutamate into the cell against a substantial concentration gradient. The driving force for concentrative uptake is provided by the cotransport of Na+ ions and the countertransport of one K+ in a step independent of the glutamate translocation step. Due to eletrogenicity of transport, the transmembrane potential can also act as a driving force. Glutamate transporters are expressed in many tissues, but are of particular importance in the brain, where they contribute to the termination of excitatory neurotransmission. Glutamate transporters can also run in reverse, resulting in glutamate release from cells. Due to these important physiological functions, glutamate transporter expression and, therefore, the transport rate, are tightly regulated. This review summarizes recent literature on the functional and biophysical properties, structure-function relationships, regulation, physiological significance, and pharmacology of glutamate transporters. Particular emphasis is on the insight from rapid kinetic and electrophysiological studies, transcriptional regulation of transporter expression, and reverse transport and its importance for pathophysiological glutamate release under ischemic conditions.

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Section: Molecular Transport Mechanismmentioning

confidence: 91%

SLC1 glutamate transporters

Grewer

Gameiro

Rauen

2013

Pflugers Arch - Eur J Physiol

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112

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“…The results suggest that the outward charge movement is hidden in the wild-type transporter because it is overcompensated by simultaneous inward movement of positive charge from glutamate translocation and Na ϩ binding to the empty and substratebound transporter. This is an important finding because glutamate binding adds to the substantial list of electrogenic partial reactions in glutamate transporters (6,27,45) in which charge movement within the membrane is distributed over several reaction steps. This includes Na ϩ binding, dissociation, K ϩ -induced relocation, and substrate translocation steps (27,46).…”

Section: Discussionmentioning

confidence: 99%

“…2, A and B) based on structural models of the open loop, glutamate-free and closed loop, glutamate-bound configurations ( Fig. 2C; based on EAAC1 homology models generated using Glt Ph as a template (18,27)). Solving the Poisson-Boltzmann equation allows the computation of the electrostatic energy of the two states (open loop and closed loop/glutamate-bound), which yields the valence of the transition, when computed as a function of the membrane potential ( Fig.…”

Section: Computational Analysis Suggests That Glutamate Binding Ismentioning

confidence: 99%

“…Electrostatic Calculations-We have used the adaptive Poisson-Boltzmann solver, APBS (25), together with the APBSmem Java routines (26) to calculate the electrostatic energies of the glutamate transporter embedded into an implicit membrane in various states (HP2 open and closed, substrate bound and unbound), as described (27). In brief, the following modified version of the linearized Poisson-Boltzmann equation was used.…”

Section: Ionic Conditions For Rapid Solution Exchange-to Test Anion-cmentioning

confidence: 99%

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Electrogenic Steps Associated with Substrate Binding to the Neuronal Glutamate Transporter EAAC1

Tanui

Tao

Silverstein

et al. 2016

Journal of Biological Chemistry

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Glutamate transporters actively take up glutamate into the cell, driven by the co-transport of sodium ions down their transmembrane concentration gradient. It was proposed that glutamate binds to its binding site and is subsequently transported across the membrane in the negatively charged form. With the glutamate binding site being located partially within the membrane domain, the possibility has to be considered that glutamate binding is dependent on the transmembrane potential and, thus, is electrogenic. Experiments presented in this report test this possibility.

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“…To further support the hypothesis co-transported cations are used to neutral the endogenous charges present in the empty transporter (34), a combination of pre-steady state concentration and voltage jump experiments with computational modeling were used. These data led to the conclusion that the negative charge generated by the movement of the empty transport is, indeed, in part compensated by the binding and translocation of Na + , H + , and K + ions (35). The compensation of endogenous transporter charges by ion binding, in addition to a defocused electric field and distribution of electrogenic steps, allows for a tightly regulated and energetically reasonable transport mechanism (Figure 2).…”

Section: Mechanism Of Transportmentioning

confidence: 99%

Excitatory amino acid transporters: Roles in glutamatergic neurotransmission

Divito¹,

Underhill²

2014

Neurochemistry International

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Excitatory amino acid transporters or EAATs are the major transport mechanism for extracellular glutamate in the nervous system. This family of five carriers not only displays an impressive ability to regulate ambient extracellular glu concentrations but also regulate the temporal and spatial profile of glu after vesicular release. This dynamic form of regulation mediates several characteristic of synaptic, perisynaptic, and spillover activation of ionotropic and metabotropic receptors. EAATs function through a secondary active, electrogenic process but also possess a thermodynamically uncoupled ligand gated anion channel activity, both of which have been demonstrated to play a role in regulation of cellular activity. This review will highlight the inception of EAATs as a focus of research, the transport and channel functionality of the carriers, and then describe how these properties are used to regulate glutamatergic neurotransmission.

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Charge Compensation Mechanism of a Na+-coupled, Secondary Active Glutamate Transporter

Abstract: Background: Reorientation of the binding sites of the glutamate transporter requires K ϩ translocation.

Cited by 29 publications

References 41 publications

SLC1 glutamate transporters

SLC1 glutamate transporters

Electrogenic Steps Associated with Substrate Binding to the Neuronal Glutamate Transporter EAAC1

Excitatory amino acid transporters: Roles in glutamatergic neurotransmission

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