Kidney International, Vol. 57 (2000), pp. 1772–1773

EDITORIAL

Molecular basis of organic anion and cation transport

The kidney and liver have the ability to take up small, try) and functional characteristics (revealed in the heter-weakly charged organic substances from the circulation ologous expression system). The article by Nakajima etand secrete them into the urine and bile fluid, respec- al in this issue of Kidney International [7] is one attempttively. Many endogenous and exogenous substances and to delineate the physiological functions of the first identi-their metabolites, xenobiotics, and drugs are eliminated fied OAT, OAT1. Histochemical studies on OAT1 ex-from the body by this system [1]. Examples of such anions pression were conducted in the perinatal period and theare hippurate, long chain fatty acids, bile salts, urate, results were correlated with functional studies. OAT1 isprostaglandins, antibiotics, and diuretics, and examples known to be localized in the basolateral membrane ofof cations are choline, catecholamines, histamine, qui- proximal tubule cells (predominantly in the S2 segment)nine, and cimetidine. Thus, an understanding of this sys- and its expression was shown to increase after birth.tem is important not only for normal physiology, but Kidney organic anion secretion is known to increase afteralso for practical clinical purposes. birth to respond to the demand from wasting of a variety

Numerous physiological studies in the kidney and liver of metabolic metabolites after cessation of placental ex-have shown the presence of many transport systems for change. This is supportive evidence for OAT1 to functionthese substances with different transport characteristics, as a transporter that is upregulated during the perinatalsubstrate specificities, and sensitivities to inhibitors [2]. period, and thus is physiologically important.One common feature in these transport systems (trans- As repeatedly shown in other cloned proteins, theporters) is a broad specificity to transporting substances, physiologic significance of the transporters in the bodythat is, multiple substances can be transported by one is confirmed by the identification of hereditary diseasestransporter. This character is striking when compared to caused by mutations of the genes encoding the transport-other transporters and ion channels. ers or demonstrating phenotypic abnormalities in gene

Molecular identification of these transporters has targeting animals (knockout mouse). Primary systemicmade rapid progress over the last five years. The isolation carnitine deficiency is an autosomal recessive disorderof the first member by expression cloning strategy [3–5] characterized by progressive cardiomyopathy, skeletalsoon allowed the identification of homologous proteins. myopathy, hypoglycemia and hyperammoniemia. ThisThree organic cation transporters have been found and disease was recently shown to be caused by mutationsnamed OCT1, OCT2, and OCT3. Similarly, three cloned in the OCTN2 gene [8]. OCTN2 is thus critical for theorganic anion transporters have been named OAT1-3. reabsorption of carnitine in the kidney. cMOAT (canali-Not surprisingly, OCTs and OATs were shown to have cular multispecific organic anion transporter), a proteinsequence similarity of about 30% and to constitute a belonging to the ABC superfamily that does not have alarge family. Another subfamily belonging to this family sequence homology to the OAT/OCT family, is anotherwith the feature of cation transport was discovered and organic anion transporter. Its gene mutations were dem-named OCTN [6]. Sequence homology in this superfam- onstrated in the patients with Dubin-Johnson syndromeily predicts similar molecular structures in these proteins: [9]. Thus, cMOAT plays a critical role in the secretiontwelve membrane spanning domains, a large extracellu- of conjugated bilirubin into the bile. These are the onlylar loop between helixes 1 and 2, and a large intracellular two diseases attributed to defects of the organic sub-loop between helixes 6 and 7. Thus, there are not very stance transporter genes, and no reports are availablemany structural differences between organic anion and for gene targeting animal models of these genes. Furthercation transporters. studies in this area are eagerly awaited.

Molecular identification was a great advance, but it What are the benefits from the molecular identifica-raised new questions. What is the specific physiological tion of OATs and OCTs? First, an understanding of therole for each transporter in the body? The role of each

transports of organic substances becomes more clear andcloned transporter can be speculated by its localization

tangible for general nephrologists and researchers in(shown by in situ hybridization and immunohistochemis-other fields. Previous description of functional character-istics of proposed transport systems were enormously

Key words: transporter, ion channels, OAT, cloning. complicated and hard to integrate. Molecular basedknowledge will make it easy to understand the interac- 2000 by the International Society of Nephrology

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Editorial 1773

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much less attention than the transport of non-organic Int 57:1608–1616, 20008. Nezu J, Tamai I, Oku A, Ohashi R, Yabuuchi H, Hashimoto N,ions (Na, K and Cl, for example), but now it has a sturdy

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Reprint requests to Sei Sasaki, M.D., Internal Medicine II, Tokyo 10. Koepsell H, Gorboulev V, Arndt P: Molecular pharmacologyMedical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo of organic cation transporters in kidney. J Membr Biol 167:103–117,113-8519 Japan. E-mail: ssasaki.med2@med.tmd.ac.jp 1999