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Organic anion transporters (OATs) belong to the largest family of secondary active membrane transporters: the major facilitator superfamily (MFS), which is conserved from bacteria to mammals [1–3]. MFS transporters function as transmembrane uniporters, symporters, and antiporters, and transport a wide range of hydrophilic and amphiphilic substrates, including inorganic ions (e.g., Na⁺, Cl^–, HCO₃ ^–), endogenous metabolites (e.g., amino acids, sugars, neurotransmitters), signaling molecules (cyclic nucleotides, prostaglandins), and xenobiotics (drugs and toxins). Within this MFS superfamily, the OATs are members of Solute Carrier 22 (SLC22), a family of solute carriers which currently, in humans, consists of over 30 named transporters expressed in most barrier epithelia in mammals, including the kidney, choroid plexus, blood–brain barrier, biliary tract, intestine, retinal–blood barrier, olfactory mucosa, blood–testis barrier, and others [4]. These structurally similar proteins mediate the partitioning of a wide variety of compounds (e.g., endogenous metabolites, signaling molecules, natural products, endogenous toxins, environmental toxins, and drugs) into these various body fluid and tissue compartments, and they have been categorized based on the specific type of substrate which they transport, as well as sequence homology, including the OATs, as well as the organic cation transporters (OCTs), carnitine transporters (OCTNs), unknown solute transporters (USTs), and fly‐like putative transporters (Flipts) [5–12].

Until recently, much of the physiological knowledge concerning OAT function has been found by studying prototypical substrates, such as p‐aminohippurate (PAH) and estrone‐3‐sulfate. The “classical” organic anion (OA) or organic acid secretory system is thought to be fundamentally involved in the excretion of common drugs, toxins, and endogenous metabolites into the urine, thereby maintaining the equilibrium of anionic metabolites in the body. OATs, the proteins that underlie the OA secretory system, are an example of secondary (and/or tertiary) active membrane transporters, which move substrates across the cell membrane by utilizing a transmembrane electrochemical gradient of the substrate itself or of another solute [13]. To date, over 10 OAT family members have been clearly identified in humans and rodents (Table 4.1). Several orphan family members have been identified as well and are likely to be OATs [6].

Over the past several years, there has been considerable progress in understanding the molecular basis and consequence of OAT‐mediated transport through the utilization of system biology approaches combining large data sets from transcriptomic and metabolomic studies [11]. Furthermore, these transporters have also been found to be present in numerous epithelial barrier tissues other than the kidney, including the olfactory mucosa, liver, choroid plexus, retina, placenta, and circulating blood cells, which potentially implicates OATs more broadly in remote communication processes. Moreover, the completed genome sequencing in several species has uncovered unique features of the chromosomal organization of SLC22 genes, enabling a deeper picture of the OATs at the molecular, evolutionary, and regulatory level [9, 12, 27].

TABLE 4.1 OAT family members a

Protein name (gene symbol)	Prototypical substrate(s)	Transport mechanism	Human tissue distribution	Membrane localization	Identified species	Gender difference	Human gene locus
OAT1 (SLC22A6)	PAH	OA/DC exchange	Kidney	Basolateral	Human, mouse, rat, pig, flounder, Caenorhabditis elegans	(Rat) M > F	11q12.3
OAT2 (SLC22A7)	PAH	PAH/anion exchange	Liver, kidney	Basolateral in human	Human, mouse, rat	Species dependent	6q21.1‐2
OAT3 (SLC22A8)	Estrone‐3‐sulfate	OA/DC exchange	Kidney, brain, testis	Basolateral	Human, mouse, rat, pig, rabbit	(Rat) M > F	11q12.3
OAT4 (SLC22A11)	Estrone‐3‐sultate	OA/DC exchange	Placenta, kidney, brain	Apical	Human	Unknown	11q13.1
Oat5 (Slc22a19)	Ochratoxin A	Exchanger	—	Apical	Mouse, rat	Unknown	—
Oat6 (Slc22a20)	Estrone‐3‐sulfate	Exchanger	—	Unknown	Mouse, rat	Unknown	11q13.1b
OAT7 (SLC22A9)	Estrone‐3‐sulfate	OA/DC exchange	Liver	Sinusoidal	Human	Unknown	11q12.3
Rat Oat8 (Slc22a25)	Ochratoxin A	OA/DC exchange	—	Apical	Rat	Unknown	—
Mouse Oat9 (Slc22a27)	Carnitine	unknown	—	Apical	Mouse	Unknown	—
OAT10 (SLC22A13)	Nicotine	Nicotine/anion exchange	Kidney, brain, colon	Apical	Human, rat	(Rat) F > M	3p22.2
URAT1 (SLC22A12)	Urate	Urate/anion exchange	Kidney	Apical	Human, mouse	(Mouse) M > F	11q13.1

Abbreviations: OA, organic anion; DC, dicarboxylic acid.

^a Information in this Table from references [9, 10,14–26].

^b A partial transcript in human.

In what follows, after providing basic information about the OATs and considering their pharmacological and toxicological roles, we place a major emphasis on new data revealing their roles in regulation of endogenous physiology and the intracellular post‐translational modifications that impact their expression and function. We cover their roles in handling of natural products. We then discuss their roles in pathophysiology, particularly in the handling of uremic toxins of chronic kidney disease (CKD). A major organizing principle of the chapter is the role of OATs in “remote sensing and signaling” in the service of inter‐organ cross talk and inter‐organismal communication. We thus discuss the Remote Sensing and Signaling Theory, which applies not only to OATs but other drug transporters discussed throughout this book.