PNAS：王松灵等发现细胞膜硝酸盐转运通道

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近日，首都医科大学教授王松灵课题组与美国国立卫生研究院、北京市肿瘤研究所课题组合作，首次发现哺乳类动物细胞膜的硝酸盐转运通道。相关论文发表在美国《国家科学院院刊》（<em>PNAS</em>）上。

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硝酸盐是自然界广泛存在的一种无机物，上世纪80年代，学者们发现机体可以内源性产生硝酸盐。尽管硝酸盐与肿瘤的关系一直是学者关注的重要领域，但近年来的研究发现，人体可还原硝酸盐，转化为亚硝酸盐及一氧化氮，从而发挥重要的生理功能。而机体是如何转运硝酸盐并发挥功能的机理尚不清楚。

体内循环的硝酸盐经硝酸盐还原为亚硝酸盐，进而产生的一氧化氮在维持全身硝酸根离子和一氧化氮平衡中起着重要作用，机体内25%的硝酸盐是由唾液腺摄取分泌至唾液而进入胃肠血液再循环。王松灵课题组的研究表明，腮腺是机体调节代谢硝酸盐的重要器官。课题组利用唾液腺模式器官，通过国内外合作研究，以体外细胞学、动物实验及唾液酸转运蛋白（Sialin）突变所致疾病患者和对照组研究为基础，发现了Sialin是唾液腺细胞膜硝酸盐的转运通道。进一步研究证实，经Sialin转运的硝酸盐在细胞内可转化为一氧化氮，Sialin在包括脑、肝、肾、脾在内的机体重要脏器广泛高表达，可能具有潜在的生理意义和临床应用前景。

细胞内经一氧化氮合成酶产生一氧化氮的功能具有重要临床意义，细胞在乏氧及酸性条件下经合成酶产生的一氧化氮明显减少，会启动补偿性系统，产生一氧化氮来维持细胞的功能。该研究是首次发现哺乳类动物细胞膜的硝酸盐转运通道，在机体硝酸盐循环代谢及在维持亚硝酸盐及一氧化氮稳态方面有重要作用。 
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<a title="" href="http://dx.doi.org/10.1073/pnas.1116633109" target="_blank">doi:10.1073/pnas.1116633109</a>
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<br/><strong>Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane</strong><br/>


Lizheng Qina,1, Xibao Liub,1, Qifei Suna, Zhipeng Fana, Dengsheng Xiaa, Gang Dinga, Hwei Ling Ongb, David Adamsc, William A. Gahlc, Changyu Zhengb, Senrong Qia, Luyuan Jina, Chunmei Zhanga, Liankun Gud, Junqi Hee, Dajun Dengd,2, Indu S. Ambudkarb,2, and Songlin Wanga,e,2

In vivo recycling of nitrate (NO3?) and nitrite (NO2?) is an important alternative pathway for the generation of nitric oxide (NO) and maintenance of systemic nitrate–nitrite–NO balance. More than 25% of the circulating NO3? is actively removed and secreted by salivary glands. Oral commensal bacteria convert salivary NO3? to NO2?, which enters circulation and leads to NO generation. The transporters for NO3? in salivary glands have not yet been identified. Here we report that sialin (SLC17A5), mutations in which cause Salla disease and infantile sialic acid storage disorder (ISSD), functions as an electrogenic 2NO3?/H+ cotransporter in the plasma membrane of salivary gland acinar cells. We have identified an extracellular pH-dependent anion current that is carried by NO3? or sialic acid (SA), but not by Br?, and is accompanied by intracellular acidification. Both responses were reduced by knockdown of sialin expression and increased by the plasma membrane-targeted sialin mutant (L22A-L23A). Fibroblasts from patients with ISSD displayed reduced SA- and NO3?-induced currents compared with healthy controls. Furthermore, expression of disease-associated sialin mutants in fibroblasts and salivary gland cells suppressed the H+-dependent NO3? conductance. Importantly, adenovirus-dependent expression of the sialinH183R mutant in vivo in pig salivary glands decreased NO3? secretion in saliva after intake of a NO3?-rich diet. Taken together, these data demonstrate that sialin mediates nitrate influx into salivary gland and other cell types. We suggest that the 2NO3?/H+ transport function of sialin in salivary glands can contribute significantly to clearance of serum nitrate, as well as nitrate recycling and physiological nitrite-NO homeostasis.

<br/>来源：中国科学报

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