Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane.
In vivo recycling of nitrate (NO(3)(-)) and nitrite (NO(2)(-)) 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 NO(3)(-) is actively removed and secreted by salivary glands. Oral commensal bacteria convert salivary NO(3)(-) to NO(2)(-), which enters circulation and leads to NO generation. The transporters for NO(3)(-) 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 NO(3)(-) 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 NO(3)(-)-induced currents compared with healthy controls. Furthermore, expression of disease-associated sialin mutants in fibroblasts and salivary gland cells suppressed the H(+)-dependent NO(3)(-) conductance. Importantly, adenovirus-dependent expression of the sialinH183R mutant in vivo in pig salivary glands decreased NO(3)(-) secretion in saliva after intake of a NO(3)(-)-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.
Salivary Gland Disease Center and Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction,  Capital Medical University School of Stomatology, Beijing 100050,  China.
Lizheng
L
Qin
Xibao
X
Liu
Qifei
Q
Sun
Zhipeng
Z
Fan
Dengsheng
D
Xia
Gang
G
Ding
Hwei Ling
HL
Ong
David
D
Adams
William A
WA
Gahl
Changyu
C
Zheng
Senrong
S
Qi
Luyuan
L
Jin
Chunmei
C
Zhang
Liankun
L
Gu
Junqi
J
He
Dajun
D
Deng
Indu S
IS
Ambudkar
Songlin
S
Wang
D000143:Acids / Q000378:metabolism; D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D027321:Anion Transport Proteins / Q000378:metabolism*; D000838:Anions; D001692:Biological Transport; D002462:Cell Membrane / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D042541:Intracellular Space / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D000091285:Nitrate Transporters; D009566:Nitrates / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism*; D011522:Protons; D029461:Sialic Acid Storage Disease / Q000378:metabolism; D013363:Submandibular Gland / Q000166:cytology / Q000378:metabolism; D034421:Sus scrofa; D027981:Symporters / Q000235:genetics / Q000378:metabolism*
D000143:Acids; D027321:Anion Transport Proteins; D000838:Anions; D000091285:Nitrate Transporters; D009566:Nitrates; D027361:Organic Anion Transporters; D011522:Protons; D027981:Symporters; C421224:sialic acid transport proteins; D019158:N-Acetylneuraminic Acid