Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Biochemistry
2021 Aug 17;6032:2463-2470. doi: 10.1021/acs.biochem.1c00375.
Show Gene links
Show Anatomy links
Allosteric Inhibition of a Vesicular Glutamate Transporter by an Isoform-Specific Antibody.
Eriksen J
,
Li F
,
Stroud RM
,
Edwards RH
.
???displayArticle.abstract???
The role of glutamate in excitatory neurotransmission depends on its transport into synaptic vesicles by the vesicular glutamate transporters (VGLUTs). The three VGLUT isoforms exhibit a complementary distribution in the nervous system, and the knockout of each produces severe, pleiotropic neurological effects. However, the available pharmacology lacks sensitivity and specificity, limiting the analysis of both transport mechanism and physiological role. To develop new molecular probes for the VGLUTs, we raised six mouse monoclonal antibodies to VGLUT2. All six bind to a structured region of VGLUT2, five to the luminal face, and one to the cytosolic. Two are specific to VGLUT2, whereas the other four bind to both VGLUT1 and 2; none detect VGLUT3. Antibody 8E11 recognizes an epitope spanning the three extracellular loops in the C-domain that explains the recognition of both VGLUT1 and 2 but not VGLUT3. 8E11 also inhibits both glutamate transport and the VGLUT-associated chloride conductance. Since the antibody binds outside the substrate recognition site, it acts allosterically to inhibit function, presumably by restricting conformational changes. The isoform specificity also shows that allosteric inhibition provides a mechanism to distinguish between closely related transporters.
Anne,
Vesicular neurotransmitter transporters: mechanistic aspects.
2014,
Pubmed
Bellocchio,
Uptake of glutamate into synaptic vesicles by an inorganic phosphate transporter.
2000,
Pubmed
Cao,
SLC17A9 protein functions as a lysosomal ATP transporter and regulates cell viability.
2014,
Pubmed
Chang,
The dual role of chloride in synaptic vesicle glutamate transport.
2018,
Pubmed
Cheret,
Vesicular Glutamate Transporters (SLCA17 A6, 7, 8) Control Synaptic Phosphate Levels.
2021,
Pubmed
Drew,
Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS).
2021,
Pubmed
Edwards,
The neurotransmitter cycle and quantal size.
2007,
Pubmed
El Mestikawy,
From glutamate co-release to vesicular synergy: vesicular glutamate transporters.
2011,
Pubmed
Eriksen,
The mechanism and regulation of vesicular glutamate transport: Coordination with the synaptic vesicle cycle.
2020,
Pubmed
Eriksen,
Protons Regulate Vesicular Glutamate Transporters through an Allosteric Mechanism.
2016,
Pubmed
Foster,
Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders.
2017,
Pubmed
Fremeau,
VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate.
2004,
Pubmed
Fremeau,
The expression of vesicular glutamate transporters defines two classes of excitatory synapse.
2001,
Pubmed
Fremeau,
The identification of vesicular glutamate transporter 3 suggests novel modes of signaling by glutamate.
2002,
Pubmed
Gras,
A third vesicular glutamate transporter expressed by cholinergic and serotoninergic neurons.
2002,
Pubmed
Herzog,
The existence of a second vesicular glutamate transporter specifies subpopulations of glutamatergic neurons.
2001,
Pubmed
Leano,
Structures suggest a mechanism for energy coupling by a family of organic anion transporters.
2019,
Pubmed
Li,
Ion transport and regulation in a synaptic vesicle glutamate transporter.
2020,
Pubmed
Martineau,
VGLUT1 functions as a glutamate/proton exchanger with chloride channel activity in hippocampal glutamatergic synapses.
2017,
Pubmed
Maycox,
Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes.
1988,
Pubmed
Moechars,
Vesicular glutamate transporter VGLUT2 expression levels control quantal size and neuropathic pain.
2006,
Pubmed
Moriyama,
Vesicular L-glutamate transporter in microvesicles from bovine pineal glands. Driving force, mechanism of chloride anion activation, and substrate specificity.
1995,
Pubmed
Pietrancosta,
Molecular, Structural, Functional, and Pharmacological Sites for Vesicular Glutamate Transporter Regulation.
2020,
Pubmed
Preobraschenski,
Vesicular glutamate transporters use flexible anion and cation binding sites for efficient accumulation of neurotransmitter.
2014,
Pubmed
Preobraschenski,
Dual and Direction-Selective Mechanisms of Phosphate Transport by the Vesicular Glutamate Transporter.
2018,
Pubmed
Roseth,
Uptake of L-glutamate into rat brain synaptic vesicles: effect of inhibitors that bind specifically to the glutamate transporter.
1995,
Pubmed
Schenck,
Generation and Characterization of Anti-VGLUT Nanobodies Acting as Inhibitors of Transport.
2017,
Pubmed
Schenck,
A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles.
2009,
Pubmed
Seal,
Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3.
2008,
Pubmed
Shioi,
Artificially imposed electrical potentials drive L-glutamate uptake into synaptic vesicles of bovine cerebral cortex.
1990,
Pubmed
Tamura,
A new VGLUT-specific potent inhibitor: pharmacophore of Brilliant Yellow.
2014,
Pubmed
Wallén-Mackenzie,
Vesicular glutamate transporter 2 is required for central respiratory rhythm generation but not for locomotor central pattern generation.
2006,
Pubmed
Winter,
Glutamate uptake system in the presynaptic vesicle: glutamic acid analogs as inhibitors and alternate substrates.
1993,
Pubmed
Wojcik,
An essential role for vesicular glutamate transporter 1 (VGLUT1) in postnatal development and control of quantal size.
2004,
Pubmed