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

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Abstract

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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Abbreviations

ABC:

ATP-binding cassette

Ala:

Alanine

Arg:

Arginine

Akt:

Akt/protein kinase B

CALHM1:

Calcium homeostasis modulator 1

DIDS:

Diisothiocyanatostilbene disulfonic acid

ID50:

The concentrations required for 50% inhibition

18GA:

18α-glycyrrhetinic acid

Glu:

Glutamate

Gln:

Glutamine

Lamp1:

Lysosomal-associated membrane protein 1

NMDA:

N-methyl-D-aspartic acid

NPT:

Na+-dependent phosphate transporter

PSD-95:

Post-synaptic density 95

SLC:

Solute carrier

TRP4:

The short transient potential channel 4

VAchT:

Vesicular acetylcholine transporter

VEAT:

Vesicular excitatory amino acid transporter

VGAT:

Vesicular GABA transporter

VGLUT:

Vesicular glutamate transporter

VMAT:

Vesicular monoamine transporter

VNUT:

Vesicular nucleotide transporter

V-ATPase:

Vacuolar H+-ATPase

ΔpH:

A H+ gradient

Δψ:

The membrane potential

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Acknowledgements

We thank Prof. Nathan Nelson, Mrs. Sawako Moriyama, the late Prof. Akitsugu Yamamoto, Dr. Keisuke Sawada, and Dr. Noriko Echigo for their contributions in identification of VNUT; Misses. Satomi Moriyama and Yuika Harada for conducting the immunohistochemistry; and Prof. S. Koizumi, Drs. K. Iwatsuki, T. Miyaji, and N. Ichikawa for the valuable discussion of the content of this paper. This work was supported in part by Grants-in-Aid from the Japanese Ministry of Education, Science, Sports and Culture for Scientific Research (A), and the Japan Science and Technology Agency for Japan-Israel Scientific Research Cooperation to YM, and Grants-in Aid for Young Scientists (B) to SS and MH, and Grants-in-Aid for Scientific Research (C) to MN.

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Correspondence to Yoshinori Moriyama or Masatoshi Nomura.

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Yoshinori Moriyama declares that he has no conflict of interest.

Miki Hiasa declares that she has no conflict of interest.

Shohei Sakamoto declares that he has no conflict of interest.

Hiroshi Omote declares that he has no conflict of interest.

Masatoshi Nomura declares that he has no conflict of interest.

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Moriyama, Y., Hiasa, M., Sakamoto, S. et al. Vesicular nucleotide transporter (VNUT): appearance of an actress on the stage of purinergic signaling. Purinergic Signalling 13, 387–404 (2017). https://doi.org/10.1007/s11302-017-9568-1

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  • DOI: https://doi.org/10.1007/s11302-017-9568-1

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