cDNA Cloning and Functional Expression of a Novel Rat Kidney Organic Cation Transporter, OCT2

Okuda, Masahiro; Saya, Hideyuki; Urakami, Yumiko; Takano, Mikihisa; Inui, Ken Ichi

doi:10.1006/bbrc.1996.1056

Cited by 321 publications

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“…Fig. 1 shows the deduced amino acid sequence of rat OAT3 and the alignment with those of rat OAT1, OAT2, OCT1, and OCT2 (20). The amino acid sequence of OAT3 shows 49, 39, 36, and 35% identity to those of rat OAT1, OAT2, OCT1,and OCT2, respectively (Table I).…”

Section: Resultsmentioning

confidence: 99%

Molecular Cloning and Characterization of a New Multispecific Organic Anion Transporter from Rat Brain

Kusuhara¹,

Sekine²,

Utsunomiya‐Tate³

et al. 1999

Journal of Biological Chemistry

440

479

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A cDNA encoding the new member of the multispecific organic anion transporter family, OAT3, was isolated by the reverse transcription-polymerase chain reaction cloning method. Degenerate primers were designed based on the sequences conserved among OAT1, OAT2, and organic cation transporter 1 (OCT1), and reverse transcription-polymerase chain reaction was performed using rat brain poly(A)؉ RNA. The 536-amino acid protein sequence encoded by OAT3 showed 49, 39, and 36% identity to those of OAT1, OAT2, and OCT1, respectively. Northern blot analysis revealed that rat OAT3 mRNA is expressed in the liver, brain, kidney, and eye. When

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Section: Resultsmentioning

confidence: 99%

Molecular Cloning and Characterization of a New Multispecific Organic Anion Transporter from Rat Brain

Kusuhara¹,

Sekine²,

Utsunomiya‐Tate³

et al. 1999

Journal of Biological Chemistry

440

479

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“…14,15,27,28 Other members of the putative organic cation superfamily include OCT2 and rOCT1A, which have also been cloned and functionally characterized, but do not appear to be expressed in the liver. 14,[28][29][30][31] Similarly, homologous cDNAs that encode for a polyspecific renal anion transporter, OAT1 (also known as the paraaminohippurate transporter), have been recently identified, but also appear to be kidney-specific. [32][33][34] The rat and human OCT1 are kinetically similar to a renal proximal tubule and hepatocellular basolateral plasma membrane TEA transporter, and functionally characterized by NMN-inhibition of organic cation uptake.…”

Section: Discussionmentioning

confidence: 99%

Cloning and functional expression of a mouse liver organic cation transporter

Green

Sterritt

et al. 1999

Hepatology

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Hepatic uptake of organic cations is essential for the metabolism and secretion of numerous endobiotics and drugs. Several hepatic organic cation transporters have been kinetically defined, yet have not been isolated or cloned. We have isolated a complementary DNA (cDNA) from both murine liver and kidney cDNA libraries (mOct1/ Slc22a1), and have functionally expressed it in Xenopus laevis oocytes. Although mOct1/Slc22a1 is homologous to previously cloned rat and human organic cation transporters, organic cation transport kinetics differed markedly. The liver and kidneys have critical roles in the secretion of drugs and endobiotics into the bile and urine. Hepatic elimination of many organic cationic drugs involves uptake across the basolateral surface of the hepatocyte, hepatic biotransformation, and canalicular secretion. 1 Previous studies in the intact rat, isolated perfused rat liver, and isolated hepatocytes show that the hepatobiliary transport of organic cations is carrier-mediated. [2][3][4] In addition, the organic cation choline is an essential nutrient and precursor for the synthesis of phospholipids. Hepatic choline levels are approximately 100-fold greater than blood concentrations, and de novo choline synthesis is minimal, suggesting the existence of a transport mechanism for hepatic choline uptake. 5,6 Several organic cation transporters have been kinetically defined on the plasma membrane of hepatocytes and in lysosomes. Functional studies in rat liver plasma membrane vesicles have shown at least two distinct organic cation:H ϩ exchangers, and two electrogenic organic cation transporters. [7][8][9][10][11][12][13] The complementary DNA (cDNA) encoding for the rat electrogenic polyspecific transporter (OCT1) has been isolated using functional expression cloning in Xenopus laevis oocytes, and assaying n-methyl-nicotinamide (NMN)-inhibitable uptake of the model quaternary organic cation tetraethylammonium (TEA). 14 A human homologue of rat OCT1 was recently cloned that transports 1-methyl-4-phenylpyridinium (MPP ϩ ), and uptake is also inhibited by the organic cation NMN. 15 In this study, we have isolated a murine cDNA (mOct1/ Slc22a1) from both liver and kidney libraries, and have functionally expressed it in X. laevis oocytes. Although mOct1/Slc22a1 is homologous with OCT1, transport kinetics differed markedly. mOct1/Slc22a1 transports several organic cations, but uptake is increased by inside:outside proton gradients, is unaffected by membrane potential differences, and is not inhibited by NMN. These data indicate that this cloned cDNA is a member of the hepatic and renal organic cation transporter family.

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“…13,14 While Oct1 messenger RNA (mRNA) is distributed throughout the liver lobule, the expression of Oct1 protein is only observed in hepatocytes surrounding the central veins. 10 Several additional members of the Oct family have now been identified, including Oct2 (Slc22a2), 12,15 Oct3 (Slc22a3), 16 and the more distantly related novel proton/organic cation transporters (Octn) Octn1 (Slc22a4) 17 and Octn2 (Slc22a5). 18 However, Oct2 is almost exclusively expressed in the basolateral membranes of proximal renal tubules and has some overlap in substrate specificity with Oct1, 12,15 whereas Oct3 seems to be mainly expressed in the placenta and shows less overlap in substrate specificity with Oct1.…”

mentioning

confidence: 99%

“…10 Several additional members of the Oct family have now been identified, including Oct2 (Slc22a2), 12,15 Oct3 (Slc22a3), 16 and the more distantly related novel proton/organic cation transporters (Octn) Octn1 (Slc22a4) 17 and Octn2 (Slc22a5). 18 However, Oct2 is almost exclusively expressed in the basolateral membranes of proximal renal tubules and has some overlap in substrate specificity with Oct1, 12,15 whereas Oct3 seems to be mainly expressed in the placenta and shows less overlap in substrate specificity with Oct1. 16 Recent studies in Oct1 knockout mice further suggest that Oct1 is the major if not the only physiologically significant hepatic uptake system for small organic cations.…”

mentioning

confidence: 99%

Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis

et al. 2004

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The liver plays a major role in biotransformation and elimination of various therapeutic agents and xenobiotics, many of which are organic cations and substrates of the organic cation transporter 1 (Oct1, Slc22a1). Oct1 is expressed at the basolateral membranes of hepatocytes and proximal renal tubules. Although Oct1 is the major uptake mechanism in hepatocytes for many pharmaceutical compounds, little is known about the effects of liver injury on this process. Our aim was to investigate the effects of obstructive cholestasis on Oct1 expression and function in liver and kidney. The effects of bile duct ligation (BDL) on Oct1 protein, messenger RNA (mRNA) expression, and tissue localization were determined in rat liver and kidney with Western analysis, real-time reverse transcriptase-mediated polymerase chain reaction (RT-PCR), and immunofluorescence. To assess Oct1 function, the model substrate tetraethylammonium ([ 14 C]TEA) was administered intravenously to BDL and control rats and distribution of radioactivity was determined. Oct1 protein significantly decreased in cholestatic livers to 42.1 ؎ 17.7% (P < .001), 15.5 ؎ 4.7% (P < .05), and 8.6 ؎ 2.7% (P < .05) of controls after 3, 7, and 14 days, respectively, but not in kidneys. Hepatic Oct1 mRNA decreased to 77.2 ؎ 12.7%, 40.7 ؎ 8.1% (P < .05), and 50.3 ؎ 7.5% (P < .05) 3, 7, and 14 days after BDL, respectively. Tissue immunofluorescence corroborated these data. Hepatic accumulation of [ 14 C]TEA in 14-day BDL rats was reduced to 29.6 ؎ 10.9% of controls (P < .0005). In conclusion, obstructive cholestasis down-regulates Oct1 and impairs Oct1-mediated uptake in rat liver, suggesting that hepatic uptake of small cationic drugs may be impaired in cholestatic liver injury. (HEPATOLOGY 2004;39:1382-1389

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cDNA Cloning and Functional Expression of a Novel Rat Kidney Organic Cation Transporter, OCT2

Cited by 321 publications

References 0 publications

Molecular Cloning and Characterization of a New Multispecific Organic Anion Transporter from Rat Brain

Molecular Cloning and Characterization of a New Multispecific Organic Anion Transporter from Rat Brain

Cloning and functional expression of a mouse liver organic cation transporter

Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis

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