Mammalian nitrate transport: emerging roles of sialin, chloride channels, aquaporin-6, and the sodium-iodide symporter.

Nitrate (NO3-) has emerged as an important physiological reservoir of nitric oxide (NO) and as a nutritional strategy for enhancing NO bioavailability through the nitrate-nitrite-NO pathway. Despite increasing recognition of the biological and therapeutic significance of nitrate, the mechanisms governing its transport across mammalian cell membranes remain incompletely understood. As a charged anion, NO3- cannot freely diffuse across lipid bilayers and therefore requires membrane transport proteins to mediate its cellular uptake, distribution, and storage. This review critically examines the current evidence for membrane proteins implicated in mammalian nitrate transport, including solute carriers (sialin and the sodium-iodide symporter, NIS), chloride transport proteins, and aquaporin-6 (AQP6). We discuss their structural and functional properties, tissue distribution, transport mechanisms, and emerging physiological roles in nitrate homeostasis. Recent evidence indicates that nitrate not only serves as a substrate for these transport systems but also regulates their expression and function, including the proteolytic cleavage of plasma membrane sialin to generate sialin2, an intracellular nitrate sensor that activates metabolic signaling pathways. Collectively, current evidence suggests that mammalian nitrate transport is mediated by multiple, mechanistically distinct membrane proteins that function cooperatively to maintain nitrate homeostasis and nitric oxide bioavailability. A better understanding of these transport mechanisms may facilitate the optimization of dietary nitrate interventions and the development of nitrate-based therapeutic strategies.