Sialin ( SLC17A5 ) functions as a nitrate transporter in the plasma membrane

Abstract

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 ( SLC17A 5 ), 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.

Improvement in blood pressure after short-term inorganic nitrate supplementation is attenuated in cigarette smokers compared to non-smoking controls

“…Collectively, these findings lend support to the notion that NO 3 -and SCN -share a common salivary transporter(s), possibly sialin [54], and that SCN -can competitively inhibit salivary NO 3 -uptake.…”

Sulfite Oxidase Catalyzes Single-Electron Transfer at Molybdenum Domain to Reduce Nitrite to Nitric Oxide

“…the salivary glands and concentrated 10-to 20-fold in saliva, providing a route for entero-salivary recycling of nitrate (30,34,52). Symbiotic bacteria in the oral cavity effectively reduce nitrate to nitrite, which is further reduced to NO in the acidic stomach or systemically absorbed (30,34,50).…”

Nitrate transport in salivary glands with implications for NO homeostasis

“…The work by Qin et al (4) proposes that sialin functions as the major NO 3 − uptake system in salivary gland cells; however, a remaining question is how this nitrate is further transported to saliva through the apical portion of the cells. Sialin seems to be a versatile anion transporter that also mediates H + -dependent transport of NO 2 − , aspartate, and glutamate.…”

“…The mechanism behind this massive nitrate accumulation in saliva has remained elusive. In PNAS, the work by Qin et al (4) reports that the protein sialin can function as an effective nitrate transporter. These results are of considerable interest, especially in light of recent research suggesting a role for salivary nitrate transport and metabolism in physiological regulation of systemic NO homeostasis (5,6).…”