Inhibitors of the Glutamate Vesicular Transporter (VGLUT)

Thompson, Charles M.; Davis, Erin S.; Carrigan, Christina N.; Cox, Holly D.; Bridges, Richard J.; Gerdes, John M.

doi:10.2174/0929867054637635

Cited by 68 publications

(69 citation statements)

References 53 publications

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“…Evans blue and DIDS strongly inhibit VNUT, with ID50s of 40 nM and 1.5 μM, respectively. They also inhibit other SLC17 members, anion channels, and ion-transporting ATPases, with inhibition by some of these compounds being irreversible under natural circumstances [134,135]. Therefore, when these compounds are used to characterize the types of ATP release, researchers must remember that these compounds are not specific to the target protein.…”

Section: Development Of a Vesicular Atp Release Blockermentioning

confidence: 99%

Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling

Moriyama

Hiasa

Sakamoto³

et al. 2017

Purinergic Signalling

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Vesicular storage of ATP is one of the processes initiating purinergic chemical transmission. Although an active transport mechanism was postulated to be involved in the processes, a transporter(s) responsible for the vesicular storage of ATP remained unidentified for some time. In 2008, SLC17A9, the last identified member of the solute carrier 17 type I inorganic phosphate transporter family, was found to encode the vesicular nucleotide transporter (VNUT) that is responsible for the vesicular storage of ATP. VNUT transports various nucleotides in a membrane potential-dependent fashion and is expressed in the various ATP-secreting cells. Mice with knockout of the VNUT gene lose vesicular storage and release of ATP from neurons and neuroendocrine cells, resulting in blockage of the initiation of purinergic chemical transmission. Thus, VNUT plays an essential role in the vesicular storage and release of ATP. The VNUT knockout mice exhibit resistance for neuropathic pain and a therapeutic effect against diabetes by way of increased insulin sensitivity. Thus, VNUT inhibitors and suppression of VNUT gene expression may be used for therapeutic purposes through suppression of purinergic chemical transmission. This review summarizes the studies to date on VNUT and discusses what we have learned about the relevance of vesicular ATP release as a potential drug target.

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Section: Development Of a Vesicular Atp Release Blockermentioning

confidence: 99%

Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling

Moriyama

Hiasa

Sakamoto³

et al. 2017

Purinergic Signalling

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“…4D). The ATP uptake was greatly inhibited by 4,4Ј-diisothiocyanatostilbene-2,2Ј-disulfonate (DIDS), an inhibitor of VGLUT (23). The concentration required for ID 50 was 1.5 M (Fig.…”

Section: Didsmentioning

confidence: 99%

Identification of a vesicular nucleotide transporter

Sawada

Echigo

Juge

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

374

457

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ATP is a major chemical transmitter in purinergic signal transmission. Before secretion, ATP is stored in secretory vesicles found in purinergic cells. Although the presence of active transport mechanisms for ATP has been postulated for a long time, the proteins responsible for its vesicular accumulation remains unknown. The transporter encoded by the human and mouse SLC17A9 gene, a novel member of an anion transporter family, was predominantly expressed in the brain and adrenal gland. The mouse and bovine counterparts were associated with adrenal chromaffin granules. Proteoliposomes containing purified transporter actively took up ATP, ADP, and GTP by using membrane potential as the driving force. The uptake properties of the reconstituted transporter were similar to that of the ATP uptake by synaptic vesicles and chromaffin granules. Suppression of endogenous SLC17A9 expression in PC12 cells decreased exocytosis of ATP. These findings strongly suggest that SLC17A9 protein is a vesicular nucleotide transporter and should lead to the elucidation of the molecular mechanism of ATP secretion in purinergic signal transmission.ATP ͉ chromaffin granule ͉ purinergic signaling ͉ storage and exocytosis ͉ synaptic vesicle V esicular storage and subsequent exocytosis of neurotransmitters is essential for chemical transmission in neurons and endocrine cells. Thus far four distinct classes of transporters are known to participate in the uptake of neurotransmitters into neuronal synaptic vesicles and secretory granules in endocrine cells. These are vesicular monoamine transporters, vesicular acetylcholine transporters, vesicular inhibitory amino acid transporters, and vesicular glutamate transporters (VGLUTs) (1-7). These vesicular transporters mediate the active accumulation of their respective neurotransmitters through an electrochemical gradient of protons across the membrane generated by vacuolar proton-ATPase. ATP is stored in secretory vesicles and subsequently exocytosed, which leads to the various purinergic responses, such as central control of autonomic functions, pain and mechanosensory transduction, neural-glial interactions, control of vessel tone and angiogenesis, and platelet aggregation through purinoceptors, thus establishing its role as a chemical transmitter (8)(9)(10)(11)(12). Because the concentration of nucleotides in the vesicles was maintained at Ϸ0.1-1 M, an active transport mechanisms to accumulate nucleotides has been postulated (8-18). Although evidence increasingly supports the presence of a vesicular ATP transporters in secretory vesicles such as synaptic vesicles and adrenal chromaffin granules (13-19), the protein responsible for the ATP accumulation has not yet been identified.Here, we report the expression and function of human and mouse SLC17A9, an isoform of the SLC17 phosphate transporter family. We present evidence that the SLC17A9 protein acts as a vesicular nucleotide transporter (VNUT) and that it plays an essential role in vesicular storage of ATP in the ATP-secreting cells. Results a...

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“…RB, a polyhalogenated fluorescein analog, is a potent inhibitor of glutamate uptake into synaptic vesicles via allosteric modulation of VGLUTs (Ogita et al, 2001;Thompson et al, 2005). VGLUTs are capable of mediating cellular efflux of glutamate.…”

Section: Involvement Of Glur5 Kainate Receptors In the Regulation Of mentioning

confidence: 99%

Age‐dependent enhancement of inhibitory synaptic transmission in CA1 pyramidal neurons via GluR5 kainate receptors

Cui

Alkon

2009

Hippocampus

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Changes in hippocampal synaptic networks during aging may contribute to age-dependent compromise of cognitive functions such as learning and memory. Previous studies have demonstrated that GABAergic synaptic transmission exhibits age-dependent changes. To better understand such age-dependent changes of GABAergic synaptic inhibition, we performed whole-cell recordings from pyramidal cells in the CA1 area of acute hippocampal slices on aged (24-26 months old) and young (2-4 months old) Brown-Norway rats. We found that the frequency and amplitude of spontaneous inhibitory postsynaptic current (IPSCs) were significantly increased in aged rats, but the frequency and amplitude of mIPSCs were decreased. Furthermore, the regulation of GABAergic synaptic transmission by GluR5 containing kainate receptors was enhanced in aged rats, which was revealed by using LY382884 (a GluR5 kainate receptor antagonist) and ATPA (a GluR5 kainate receptor agonist). Moreover, we demonstrated that vesicular glutamate transporters are involved in the kainate receptor dependent regulation of sIPSCs. Taken together, these results suggest that GABAergic synaptic transmission is potentiated in aged rats, and GluR5 containing kainate receptors regulate the inhibitory synaptic transmission through endogenous glutamate. These alterations of GABAergic input with aging could contribute to age-dependent cognitive decline.

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Inhibitors of the Glutamate Vesicular Transporter (VGLUT)

Cited by 68 publications

References 53 publications

Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling

Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling

Identification of a vesicular nucleotide transporter

Age‐dependent enhancement of inhibitory synaptic transmission in CA1 pyramidal neurons via GluR5 kainate receptors

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