Is the vesicular nucleotide transporter a molecular target of eicosapentaenoic acid?
Is the vesicular nucleotide transporter a molecular target of eicosapentaenoic acid?
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DOI：
10.3389/fphar.2022.1080189
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发表时间：
2022
影响因子：
5.6
通讯作者：
Nomura, Masatoshi
中科院分区：
文献类型：
--
作者：
Moriyama, Yoshinori;Hasuzawa, Nao;Nomura, Masatoshi
关键词：
囊泡核苷酸转运蛋白（Vesicular nucleotide transporter， VNUT）是分泌性囊泡中核苷酸的活性转运蛋白，负责ATP的囊泡储存，并在嘌呤能化学传递中发挥重要作用。抑制VNUT可使分泌囊泡腔内ATP浓度降低，进而导致囊泡内ATP释放减少，从而阻断嘌呤能化学传递。最近，Miyaji和同事报道了二十碳五烯酸（eicosapentaenoic acid， EPA）是一种有效的VNUT抑制剂，通过抑制ATP的囊泡储存和释放，有效治疗神经性和炎症性疼痛和胰岛素抵抗。然而，我们的验证研究表明，在牛肾上腺染色质颗粒膜泡中，EPA抑制质子跨膜电化学梯度的形成，50%抑制浓度（IC50）为1.0 μM，而不影响康那霉素b敏感的atp酶活性。本质上，含有纯化液泡H+- atp酶的蛋白脂质体获得了类似的结果。与上述观察结果一致，EPA抑制了染色质颗粒膜囊对ATP和多巴胺的依赖性摄取，其ID50分别为1.2 μM和1.0 μM。此外，EPA抑制小鼠脑突触囊泡对atp依赖性的l -谷氨酸的摄取，ID50为0.35 μM。这些结果表明，无论是否存在VNUT，亚μ m的EPA都可以作为质子导体，增加质子穿过膜的通透性，从而非特异性地抑制神经递质的囊泡储存。因此，EPA对化学物质传播的影响范围可能比提议的要大。
Vesicular nucleotide transporter (VNUT), an active transporter for nucleotides in secretory vesicles, is responsible for the vesicular storage of ATP and plays an essential role in purinergic chemical transmission. Inhibition of VNUT decreases the concentration of ATP in the luminal space of secretory vesicles, followed by decreased vesicular ATP release, resulting in the blockade of purinergic chemical transmission. Very recently, Miyaji and colleagues reported that eicosapentaenoic acid (EPA) is a potent VNUT inhibitor and effective in treating neuropathic and inflammatory pain and insulin resistance through inhibition of vesicular storage and release of ATP. However, our validation study indicated that, in bovine adrenal chromaffin granule membrane vesicles, EPA inhibited the formation of an electrochemical gradient of protons across the membrane with the concentration of 50% inhibition (IC50) being 1.0 μM without affecting concanamycin B-sensitive ATPase activity. Essentially, similar results were obtained with proteoliposomes containing purified vacuolar H+-ATPase. Consistent with these observations, EPA inhibited the ATP-dependent uptakes of ATP and dopamine by chromaffin granule membrane vesicles, with ID50 being 1.2 and 1.0 μM, respectively. Furthermore, EPA inhibited ATP-dependent uptake of L-glutamate by mouse brain synaptic vesicles with ID50 being 0.35 μM. These results indicate that EPA at sub-μM acts as a proton conductor and increases proton permeability across the membrane, regardless of the presence or absence of VNUT, thereby inhibiting non-specifically the vesicular storage of neurotransmitters. Thus, EPA may affect a broader range of chemical transmission than proposed.
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DOI：
10.1073/pnas.2122158119
发表时间：
2022-07-26
影响因子：
11.1
作者：
Kato, Yuri;Ohsugi, Kengo;Fukuno, Yuto;Iwatsuki, Ken;Harada, Yuika;Miyaji, Takaaki
通讯作者：
Miyaji, Takaaki
影响因子：
11.1
作者：
Kinoshita M;Hirayama Y;Fujishita K;Shibata K;Shinozaki Y;Shigetomi E;Takeda A;Le HPN;Hayashi H;Hiasa M;Moriyama Y;Ikenaka K;Tanaka KF;Koizumi S
通讯作者：
Koizumi S
DOI：
10.1073/pnas.1600690113
发表时间：
2016-07-12
影响因子：
11.1
作者：
Estevez-Herrera, Judith;Dominguez, Natalia;David Machado, Jose
通讯作者：
David Machado, Jose
影响因子：
4.8
作者：
MORIYAMA, Y;YAMAMOTO, A
通讯作者：
YAMAMOTO, A
影响因子：
4.6
作者：
Hasuzawa N;Tatsushima K;Wang L;Kabashima M;Tokubuchi R;Nagayama A;Ashida K;Ogawa Y;Moriyama Y;Nomura M
通讯作者：
Nomura M