cDNA Sequence, Transport Function, and Genomic Organization of Human OCTN2, a New Member of the Organic Cation Transporter Family

Wu, Xiang; Prasad, Puttur D.; Leibach, Frederick H.; Ganapathy, Vadivel

doi:10.1006/bbrc.1998.8669

Cited by 316 publications

(273 citation statements)

References 28 publications

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“…Primary carnitine deficiency is caused by defective activity of the organic cation/carnitine transporter OCTN2, resulting in urinary carnitine wasting, low serum carnitine levels, and decreased intracellular carnitine accumulation (Scaglia et al 1998;Tamai et al 1998;Wu et al 1998). Carnitine is essential for the transfer of long-chain fatty acids from the cytosol to mitochondria for subsequent b-oxidation and lack of it impairs the ability to use fat as fuel during periods of fasting or stress.…”

Section: Discussionmentioning

confidence: 99%

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

et al. 2011

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Primary systemic carnitine deficiency (SCD) is an autosomal recessive disorder caused by defective cellular carnitine transport. Patients usually present with predominant metabolic or cardiac manifestations. SCD is caused by mutations in the organic cation/carnitine transporter OCTN2 (SLC22A5) gene. Mutation analysis of SLC22A5 gene was carried out in eight Turkish patients from six families. Six patients presented with signs and symptoms of heart failure, cardiomyopathy, and low plasma carnitine levels, five of them with concurrent anemia. A patient with dilated cardiomyopathy had also facial dysmorphia, microcephaly, and developmental delay. Tandem MS analyses in siblings of the patients revealed two more cases with low plasma carnitine levels. SCD diagnosis was confirmed in these two cases by mutation screening. These two cases were asymptomatic but echocardiography revealed left ventricular dilatation in one of them. Carnitine treatment was started before the systemic signs and symptoms developed in these patients. Mean value of serum carnitine levels of the patients was 2.63 AE 1.92 mmol/L at the time of diagnosis. After 1 year of treatment, carnitine values increased to 16.62 AE 5.11 (p < 0.001) and all responded to carnitine supplementation clinically.

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Section: Discussionmentioning

confidence: 99%

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

et al. 2011

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“…Despite the previous identification of various substrates for OCTN1 in in vitro experimental systems, biologically important substrates for OCTN1 in vivo have not yet been clarified. OCTN2 (SLC22A5) is another member of the OCTN family and is much more carnitine-selective (4,5). A physiologically pivotal role of OCTN2 in reabsorption of carnitine in proximal tubules has already been identified: a missense mutation in the octn2 gene of a naturally occurring mutant, juvenile visceral steatosis (jvs) mouse, or in the OCTN2 gene of humans leads to systemic carnitine deficiency (6).…”

Section: Introductionmentioning

confidence: 99%

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

et al. 2010

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Purpose: Solute carrier, OCTN1 (SLC22A4) is an orphan transporter, the physiologically important substrate of which is still unidentified. The aim of the present study was to examine physiological roles of OCTN1. Methods:We first constructed octn1 gene knockout (octn1 -/-) mice. Metabolome analysis was then performed to identify substrates in vivo. The possible association of the substrate identified with diseased conditions was further examined. Results:The metabolome analysis of blood and several organs indicated complete deficiency of a naturally occurring potent antioxidant ergothioneine in octn1 -/-mice among 112 metabolites examined.Pharmacokinetic analyses after oral administration revealed the highest distribution to small intestines and extensive renal reabsorption of [ 3 H]ergothioneine, both of which were much reduced in octn1 -/-mice.The octn1 -/-mice exhibited greater susceptibility to intestinal inflammation under the ischemia and reperfusion model. The blood ergothioneine concentration was also much reduced in Japanese patients with Crohn's disease, compared with healthy volunteers and patients with another inflammatory bowel disease, ulcerative colitis. 4Conclusions: These results indicate that OCTN1 plays a pivotal role for maintenance of systemic and intestinal exposure of ergothioneine which could be important for protective effect against intestinal tissue injuries, providing a possible diagnostic tool to distinguish the inflammatory bowel diseases.

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“…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.…”

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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 Sequence, Transport Function, and Genomic Organization of Human OCTN2, a New Member of the Organic Cation Transporter Family

Cited by 316 publications

References 28 publications

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

Identification of Mutations and Evaluation of Cardiomyopathy in Turkish Patients with Primary Carnitine Deficiency

Gene Knockout and Metabolome Analysis of Carnitine/Organic Cation Transporter OCTN1

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

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