OA − exit into the urinary luminal space ( D) is via transporters found on the apical membrane. Thus the energy driving this ”tertiary“ mechanism is the ATP consumed by the Na +-K +-ATPase in generating the sodium gradient ( C). As a secondary active membrane transporter system ( 76), the Oat-mediated entry of OA − is linked to the transmembrane electrochemical potential of dicarboxylates generated by their movement against a concentration gradient and intracellular accumulation maintained through the action of the Na +/dicarboxylate cotransporter ( B). Oat1 and Oat3 ( A), localized to the basolateral membrane of the proximal tubule cell, transport OA − across the basolateral membrane and into the cell through the exchange of dicarboxylates (DC −). B: a renal proximal tubule cell is depicted as a prototypical epithelial cell to illustrate the Oat-mediated uptake and transcellular movement of organic anionic substrates (OA −) from the blood to the urine.
Two pairs of 6-transmembrane domains are connected by a large intracellular loop and both NH 2 and COOH termini are intracellular (G, glycosylation sites P, PKC phosphorylation sites). A: illustration of the predicted topology of organic anion transporters. OAT structure and the mechanism of OAT-mediated uptake and transport of organic anions. The role of various Oat isoforms in systems physiology appears quite complex, and their ramifications are discussed in the context of remote sensing and signaling. Oats may also play a major role in interorganismal communication (via movement of small molecules across the intestine, placental barrier, into breast milk, and volatile odorants into the urine). According to the “Remote Sensing and Signaling Hypothesis,” which is elaborated in detail here, Oats may function in remote interorgan communication by regulating levels of signaling molecules and key metabolites in tissues and body fluids. Some Oats have a strong selectivity for particular signaling molecules, including cyclic nucleotides, conjugated sex steroids, odorants, uric acid, and prostaglandins and/or their metabolites. Nuclear receptors and other transcription factors, such as Hnf4α and Hnf1α, appear to regulate the expression of certain Oats in conjunction with phase I and phase II drug metabolizing enzymes. Recent metabolomics and microarray data from Oat1 and Oat3 ( Slc22a8) knockouts, as well as systems biology studies, indicate that this pathway plays a central role in the metabolism and handling of gut microbiome metabolites as well as putative uremic toxins of kidney disease. Oats are expressed in many tissues, including kidney, liver, choroid plexus, olfactory mucosa, brain, retina, and placenta. The organic anion transporter (OAT) subfamily, which constitutes roughly half of the SLC22 (solute carrier 22) transporter family, has received a great deal of attention because of its role in handling of common drugs (antibiotics, antivirals, diuretics, nonsteroidal anti-inflammatory drugs), toxins (mercury, aristolochic acid), and nutrients (vitamins, flavonoids).
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