Functional characteristics and tissue distribution pattern of organic cation transporter 2 (OCTN2), an organic cation/carnitine transporter.
ABSTRACT We have demonstrated in the present study that novel organic cation transporter (OCTN) 2 is a transporter for organic cations as well as carnitine. OCTN2 transports organic cations without involving Na(+), but it transports carnitine only in the presence of Na(+). The ability to transport organic cations and carnitine is demonstrable with human, rat, and mouse OCTN2s. Na(+) does not influence the affinity of OCTN2 for organic cations, but it increases the affinity severalfold for carnitine. The short-chain acyl esters of carnitine are also transported by OCTN2. Two mutations, M352R and P478L, in human OCTN2 are associated with loss of transport function, but the protein expression of these mutants is comparable to that of the wild-type human OCTN2. In situ hybridization in the rat shows that OCTN2 is expressed in the proximal and distal tubules and in the glomeruli in the kidney, in the myocardium, valves, and arterioles in the heart, in the labyrinthine layer of the placenta, and in the cortex, hippocampus, and cerebellum in the brain. This is the first report that OCTN2 is a Na(+)-independent organic cation transporter as well as a Na(+)-dependent carnitine transporter and that OCTN2 is expressed not only in the heart, kidney, and placenta but also in the brain.
SourceAvailable from: Takeo Nakanishi
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ABSTRACT: 1ATB0,+ is an amino acid transporter energized by transmembrane gradients of Na+ and Cl− and membrane potential. We cloned this transporter from mouse colon and expressed the clone functionally in mammalian (human retinal pigment epithelial, HRPE) cells and Xenopus laevis oocytes to investigate the interaction of carnitine and its acyl esters with the transporter.2When expressed in mammalian cells, the cloned ATB0,+ was able to transport carnitine, propionylcarnitine and acetylcarnitine. The transport process was Na+ and Cl− dependent and inhibitable by the amino acid substrates of the transporter. The Michaelis constant for carnitine was 0.83 ± 0.08 mm and the Hill coefficient for Na+ activation was 1.6 ± 0.1.3When expressed in Xenopus laevis oocytes, the cloned ATB0,+ was able to induce inward currents in the presence of carnitine and propionylcarnitine under voltage-clamped conditions. There was no detectable current in the presence of acetylcarnitine. Carnitine-induced currents were obligatorily dependent on the presence of Na+ and Cl−. The currents were saturable with carnitine and the Michaelis constant was 1.8 ± 0.4 mm. The analysis of Na+- and Cl−-activation kinetics revealed that 2 Na+ and 1 Cl− were involved in the transport of carnitine via the transporter.4These studies describe the identification of a novel function for the amino acid transporter ATB0,+. Since this transporter is expressed in the intestinal tract, lung and mammary gland, it is likely to play a significant role in the handling of carnitine in these tissues.5A Na+-dependent transport system for carnitine has already been described. This transporter, known as OCTN2 (novel organic cation transporter 2), is expressed in most tissues and transports carnitine with high affinity. It is energized, however, only by a Na+ gradient and membrane potential. In contrast, ATB0,+ is a low-affinity transporter for carnitine, but exhibits much higher concentrative capacity than OCTN2 because of its energization by transmembrane gradients of Na+ and Cl− as well as by membrane potential.The Journal of Physiology 04/2001; 532(2). · 4.38 Impact Factor
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ABSTRACT: Variations in influx transport at the blood-brain barrier might affect the concentration of psychotropic drugs at their site of action and as a consequence might alter therapy response. Furthermore, influx transporters in organs such as the gut, liver and kidney may influence absorption, distribution, and elimination. Here, we analyzed 30 commonly used psychotropic drugs using a parallel artificial membrane permeability assay. Amisulpride and sulpiride showed the lowest membrane permeability (P e < 1.5 × 10(-6) cm/s) and will require influx transport to penetrate the blood-brain barrier and other physiological barriers. We then studied the uptake of amisulpride and sulpiride by the organic cation transporters of the SLC22 family OCT1, OCT2, OCT3, OCTN1, and OCTN2 Amisulpride was found to be transported by all five transporters studied. In contrast, sulpiride was only transported by OCT1 and OCT2. OCT1 showed the highest transport ability both for amisulpride (CLint = 1.9 ml/min/mg protein) and sulpiride (CLint = 4.2 ml/min/mg protein) and polymorphisms in OCT1 significantly reduced the uptake of both drugs. Furthermore, we observed carrier-mediated uptake that was inhibitable by known OCT inhibitors in the immortalized human brain microvascular endothelial cell line hCMEC/D3. In conclusion, this study demonstrates that amisulpride and sulpiride are substrates of organic cation transporters of the SLC22 family. SLC22 transporters may play an important role in the distribution of amisulpride and sulpiride, including their ability to penetrate the blood-brain barrier.The AAPS Journal 08/2014; 16(6). DOI:10.1208/s12248-014-9649-9 · 3.91 Impact Factor
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ABSTRACT: Ulcerative colitis (UC) is one of the main types of inflammatory bowel disease, which is caused by dysregulated immune responses in genetically predisposed individuals. Several genetic factors, including interleukin and interleukin receptor gene polymorphisms and other inflammation-related genes play central role in mediating and modulating the inflammation in the human body, thereby these can be the main cause of development of the disease. It is clear these data are very important for understanding the base of the disease, especially in terms of clinical utility and validity, but summarized literature is exiguous for challenge health specialist that can used in the clinical practice nowadays. This review summarizes the current literature on inflammation-related genetic polymorphisms which are associated with UC. We performed an electronic search of Pubmed Database among publications of the last 10 years, using the following medical subject heading terms: UC, ulcerative colitis, inflammation, genes, polymorphisms, and susceptibility.