Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane
Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane
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Sialin (SLC17A5) 在质膜中充当硝酸盐转运蛋白
DOI：
10.1073/pnas.1116633109
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发表时间：
2012-08-14
影响因子：
11.1
通讯作者：
Wang, Songlin
中科院分区：
文献类型：
--
作者：
Qin, Lizheng;Liu, Xibao;Wang, Songlin
体内硝酸盐(NO3-)和亚硝酸盐(NO2-)的循环是体内产生一氧化氮(NO)和维持全身硝酸盐-亚硝酸盐-NO平衡的重要途径。超过25%的循环中的NO-3-被唾液腺主动清除和分泌。口腔共生菌将唾液中的NO3-转化为NO2-，NO2-进入循环，产生NO。唾液腺中NO3-的转运体尚未确定。在这里，我们报道了唾液酸(SLC17A5)突变，它是导致Salla病和婴儿唾液酸储存障碍(ISSD)的突变，在唾液腺腺泡细胞的质膜上起到电生2NO(3)(-)/H+共转运体的作用。我们已经发现了一种胞外pH依赖的阴离子电流，它由NO3-或唾液酸(SA)携带，而不是由BR-携带，并伴随着细胞内的酸化。这两种反应都被sialin表达下调而被质膜靶向sialin突变体(L22A-L23A)增强。与健康对照组相比，ISSD患者的成纤维细胞显示SA和NO3-诱导的电流减少。此外，在成纤维细胞和唾液腺细胞中表达与疾病相关的唾液酸突变体抑制了H+依赖的NO3-电导。重要的是，依赖于腺病毒的sialinH183R突变体在猪唾液腺中的活体表达减少了摄入富含硝酸根的饮食后唾液中硝酸根的分泌。综上所述，这些数据表明，唾液酸介导硝酸盐流入唾液腺和其他类型的细胞。我们认为唾液腺的2NO(3)(-)/H+转运功能可能有助于清除血清硝酸盐，促进硝酸盐循环和生理亚硝酸盐-NO动态平衡。
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 2NO(3)(-)/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 2NO(3)(-)/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.