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At least 991 records · Page 55Linked to original sources
PubMed1994

Cooperation between enzyme and transporter in the inner mitochondrial membrane of yeast. Requirement for mitochondrial citrate synthase for citrate and malate transport in Saccharomyces cerevisiae.

We have characterized 1,2,3-benzenetricarboxylic acid-sensitive, mersalyl-insensitive citrate uptake by mitochondria from two strains of Saccharomyces cerevisiae by describing the time course, Km and Vmax values, pH dependence, and response to inhibitors. In unloaded mitochondria from PSY142 CS1- cells, a mutant that lacks mitochondrial citrate synthase, both citrate uptake and efflux were reduced 7- and 8-fold, respectively, compared with the parental strain. No malate uptake was detectable in mitochondria from CS1- cells, while in the parental strain, uptake was 5.4 nmol/min/mg of protein. In contrast, mutations in peroxisomal citrate synthase (CS2-) or in other tricarboxylic acid cycle enzymes did not result in changes in mitochondrial citrate transport, suggesting a specific functional role for mitochondrial citrate synthase in citrate transport. More important, liposomes containing protein extracts from CS1- mitochondria showed the same citrate and malate transport rates as liposomes made from protein extracts of parental strain mitochondria. Thus, an apparently normal amount of both the citrate transporter and the dicarboxylate carrier is present in CS1- mitochondria, but both function abnormally in undisrupted mitochondria. We suggest that cooperation between the citrate transporter and mitochondrial citrate synthase is necessary for normal function of the transporter.

Biological Transport↗
PubMed1993

Absence of electron transport (Rho 0 state) restores growth of a manganese-superoxide dismutase-deficient Saccharomyces cerevisiae in hyperoxia. Evidence for electron transport as a major source of superoxide generation in vivo.

To address the possibility that electron transport is a biologically significant source of superoxide anion (O2-.) during exposure to hyperoxia in vivo, we constructed Saccharomyces cerevisiae strains with selective disruptions in the gene encoding the mitochondrial manganese-containing superoxide dismutase (Mn-SOD) and/or genes encoding proteins critical for complexes in electron transport. We hypothesized that complete absence of electron transport would restore growth in hyperoxia to a Mn-SOD-deficient yeast. We found that yeast deficient in Mn-SOD activity failed to grow normally in hyperoxia (95% O2, 5% CO2). In contrast, Mn-SOD-deficient yeast with complete absence of electron transport (the Rho 0 state) grew normally in hyperoxia. By comparison, Mn-SOD-deficient yeast which were deficient only in cytochrome-c-oxidase, the terminal step in electron transport, had only partially restored growth in hyperoxia. Our results indicate that electron transport is a major source of O2-. in vivo, and that the principal site of this O2-. production is proximal to the cytochrome-c-oxidase complex.

Electron Transport↗
PubMed1993

Characterization of the third member of the MCAT family of cationic amino acid transporters. Identification of a domain that determines the transport properties of the MCAT proteins.

We have identified the third member of a family of cationic amino acid transporters in lipopolysaccharide-stimulated murine macrophages. The deduced amino acid sequence of this transporter is the same as MCAT-2 (mouse cationic amino acid transporter-2), the low affinity transporter expressed in hepatocytes, except for a stretch of 41 amino acids that connects the eighth and ninth membrane-spanning domains. These transporters apparently result from differential splicing of transcripts from a single gene and therefore have been named MCAT-2A (hepatocyte) and MCAT-2B (macrophage). Despite their similarity, MCAT-2B is saturated at one-fifth the arginine concentration, has a lower apparent Vmax, and is more sensitive to trans-stimulation than MCAT-2. Introduction of the unique regions of MCAT-2A and MCAT-2B into the equivalent portion of the related protein, MCAT-1, created chimeric transporters with properties most like the donor of this region. Our findings suggest these 41 amino acids contain a domain that binds the amino acid substrate during its translocation across the membrane.

Amino Acid Sequence↗
PubMed1977

Membrane transport by murine lymphocytes. II. The appearance of thymidine transport in cells from concanavalin A-stimulated mice.

We have investigated membrane transport of thymidine and adenosine by bulk murine nonadherent spleen cells from animals treated with the lectin concanavalin A. Separation of cells from radioactive medium was achieved by means of the oil microfuge technique which permits incubation periods as short as 4 sec. We were able to distinguish between the membrane-linked function of transport and uptake which includes subsequent accumulation and metabolism of the transport solute. Previously we reported that cells derived from untreated mice could not be shown to translocate thymidine in a carrier-mediated fashion. In contrast, cells from concanavalin A-treated mice showed two membrane transport systems for thymidine, a high affinity system (Km = 160 micronM) and one with low affinity (Km = 4 mM). The transport of thymidine conformed to the usual criteria for membrane carrier-linked function: increased uptake with time, substrate saturability and chemical specificity. In contrast to thymidine uptake, the transport of adenosine by cells from lectin-treated mice was similar to that shown by cells from untreated animals. Thus a specific membrane-linked activity is altered differentially in the course of mitogen-effected lymphocyte stimulation. We have found that determination of DNA synthesis by the standard method gave values which were as much as 700% too high, since the counts obtained by direct precipitation with TCA of cells incubated with radio-labeled thymidine exceed the cell-associated radiolabel obtained by the rapid sampling technique. With lectin-stimulated cells, the discrepancy observed was up to three times greater. Hence the validity of the standard assay for blastogenesis must be viewed with caution.

Adenosine↗
PubMed1998

Glutathione transport in immortalized HLE cells and expression of transport in HLE cell poly(A)+ RNA-injected Xenopus laevis oocytes.

PURPOSE: To determine reduced glutathione (GSH) transport in cultured human lens epithelial cells (HLE-B3) and plasma membrane vesicles and to study the expression of GSH transport in Xenopus laevis oocytes injected with poly(A)+ RNA from HLE-B3 cells. METHODS: Confluent HLE-B3 cells pretreated with 10 mM DL-buthionine sulfoximine and 0.5 mM acivicin were used in GSH uptake studies. The uptake of 35S-GSH was performed for 30 minutes in either NaCl medium (Na+-containing) or choline chloride medium (Na+-free) at 37 degrees C and 4 degrees C. The molecular form of 35S uptake was determined by high-performance liquid chromatography. GSH uptake kinetics were studied in acivicin and buthionine sulfoximine-treated HLE-B3 cells in NaCl medium in the concentration range 0.01 microM to 50 mM. The transport of GSH and the effect of Na+ on uptake also were determined in mixed plasma membrane vesicles from HLE-B3 cells. In oocyte expression studies, HLE-B3 poly(A)+ RNA was injected into X. laevis oocytes and GSH uptake experiments were performed 3 days after injection. The uptake of 35S-GSH and GSH efflux rates were determined in HLE-B3 poly(A)+ RNA-injected oocytes. RESULTS: No significant difference was found in the uptake of 1 mM GSH+/-acivicin (17.7+/-4.3 versus 15.7+/-1.4 picomoles/min(-1) per 10(6) cells). However, GSH uptake was significantly lower in Na+-free medium compared with Na+-containing medium (10.3+/-0.7 versus 16.8+/-0.9 picomoles/min(-1) per 10(6) cells; P < 0.01). GSH uptake in NaCl medium was carrier mediated. GSH uptake showed partial sodium dependency from 5 microM to 5 mM GSH in mixed plasma membrane vesicles from HLE-B3 cells. Oocytes injected with HLE-B3 poly(A) RNA expressed uptake and efflux of GSH. Uptake showed partial Na+ dependency at various GSH concentrations. The efflux rates were approximately 30-fold higher than those in water-injected oocytes (0.48+/-0.03 versus 0.016+/-0.005 (nanomoles per hour(-1) per oocyte, respectively). The molecular form of uptake in cultured cells and in oocyte studies was predominantly as intact GSH. CONCLUSIONS: HLE-B3 cells and plasma membrane vesicles transported GSH by a carrier-mediated process. HLE-B3 poly(A)+ RNA injected X laevis oocytes expressed GSH transport. GSH uptake was partially Na+ dependent in all systems. HLE-B3 cells offer a useful model for characterizing GSH transport and for studying its regulatory role in the etiology of cataracts.

Animals↗
PubMed2001

Glial transporters for glutamate, glycine, and GABA: II. GABA transporters.

The termination of chemical neurotransmission in the central nervous system (CNS) involves the rapid removal of neurotransmitter from synapses. This is fulfilled by specific transport systems in neurons and glia, including those for gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. Glial cells express the cloned Na(+)/Cl(-)-dependent, high-affinity GABA transporters (GATs) GAT1, GAT2, and GAT3, as well as the low-affinity transporter BGT1. In situ hybridization and immunocytochemistry have revealed that each transporter shows distinct regional distribution in the brain and the retina. The neuronal vs. glial localization of the different transporters is not clear-cut, and variations according to species, neighboring excitatory synapses, and developmental stage have been reported. The localization, stoichiometry, and regulation of glial GATs are outlined, and the participation of these structures in development, osmoregulation, and neuroprotection are discussed. A decrease in GABAergic neurotransmission has been implicated in the pathophysiology of several CNS disorders, particularly in epilepsy. Since drugs which selectively inhibit glial but not neuronal GABA uptake exert anticonvulsant activity, clearly the establishment of the molecular mechanisms controlling GATs in glial cells will be an aid in the chemical treatment of several CNS-related diseases.

Animals↗
PubMed1999

A human nucleobase transporter-like cDNA (SLC23A1): member of a transporter family conserved from bacteria to mammals.

A family of related polytopic membrane proteins that mediate the transport of nucleobases has been extended to Homo sapiens by the cloning of a full-length human cDNA that encodes a nucleobase transporter-like protein. The protein is predicted to contain 11-14 transmembrane-spanning regions, exhibits 20-28% overall sequence identity to fungal and bacterial transporters, and contains a conserved signature motif found in this family. Fluorescence in situ hybridization localized the gene (HGMW-approved symbol SLC23A1) to human chromosome 20p13. Human nucleobase transporter-like mRNA was present in all tissues examined, with lower levels found in heart, skeletal muscle, and ovary. Expression of the 60-kDa cDNA-encoded protein was demonstrated by an in vitro transcription-translation approach. The identification of this nucleobase transporter-like protein will allow the further elucidation of the interaction of human cells with physiological nucleobases and pharmacologically important drugs such as 5-F-uracil, dideoxynucleosides, and acyclic nucleosides.

Amino Acid Sequence↗
PubMed1994

Glucose transport in developing rat brain: glucose transporter proteins, rate constants and cerebral glucose utilization.

Developing rat brain undergoes a series of functional and anatomic changes which affect its rate of cerebral glucose utilization (CGU). These changes include increases in the levels of the glucose transporter proteins, GLUT1 and GLUT3, in the blood-brain barrier as well as in the neurons and glia. 55 kDa GLUT1 is concentrated in endothelial cells of the blood-brain barrier, whereas GLUT3 is the predominant neuronal transporter. 45 kDa GLUT1 is in non-vascular brain, probably glia. Studies of glucose utilization with the 2-14C-deoxyglucose method of Sokoloff et al., (1977), rely on glucose transport rate constants, k1 and k2, which have been determined in the adult rat brain. The determination of these constants directly in immature brain, in association with the measurement of GLUT1, GLUT3 and cerebral glucose utilization suggests that the observed increases in the rate constants for the transport of glucose into (ki) and out of (k2) brain correspond to the increases in 55 kDa GLUT1 in the blood-brain barrier. The maturational increases in cerebral glucose utilization, however, more closely relate to the pattern of expression of non-vascular GLUT1 (45 kDa), and more specifically GLUT3, suggesting that the cellular expression of the glucose transporter proteins is rate limiting for cerebral glucose utilization during early postnatal development in the rat.

Aging↗
PubMed2004

Transport of N-acetylaspartate via murine sodium/dicarboxylate cotransporter NaDC3 and expression of this transporter and aspartoacylase II in ocular tissues in mouse.

Canavan disease is a genetic disorder associated with optic neuropathy and the metabolism of N-acetylaspartate is defective in this disorder due to mutations in the gene coding for the enzyme aspartoacylase II. Here we show that the plasma membrane transporter NaDC3, a Na+-coupled transporter for dicarboxylates, is able to transport N-acetylaspartate, suggesting that the transporter may function in concert with aspartoacylase II in the metabolism of N-acetylaspartate. Since Canavan disease is associated with ocular complications, we investigated the expression pattern of NaDC3 and aspartoacylase II in ocular tissues in mouse by in situ hybridization. These studies show that NaDC3 mRNA is expressed in the optic nerve, most layers of the retina, retinal pigment epithelium, ciliary body, iris, and lens. Aspartoacylase II mRNA is coexpressed in most of these cell types. We conclude that transport of N-acetylaspartate into ocular tissues via NaDC3 and its subsequent hydrolysis by aspartoacylase II play an essential role in the maintenance of visual function.

Amidohydrolases↗
PubMed2005

Single amino acid (482) variants of the ABCG2 multidrug transporter: major differences in transport capacity and substrate recognition.

The human ABCG2 protein is an ATP binding cassette half-transporter, which protects our cells and tissues against various xenobiotics, while overexpression of ABCG2 in tumor cells confers multidrug resistance. It has been documented that single amino acid changes at position 482 resulted in altered drug resistance and transport capacity. In this study, we have generated nine Arg-482 mutants (G, I, M, S, T, D, N, K, Y) of ABCG2, and expressed them in insect cells. All ABCG2 variants showed cell surface expression and, in isolated membranes, an ABCG2-specific ATPase activity. When methotrexate accumulation was measured in inside-out membrane vesicles, this transport was supported only by the wild-type ABCG2. In intact cells, mitoxantrone was transported by all ABCG2 variants, except by R482K. Rhodamine 123 was extruded by most of the mutants, except by R482K, Y and by wild-type ABCG2. Hoechst 33342 was pumped out from cells expressing the wild-type and all Arg-482 variants, but not from those expressing R482K and Y. Our study demonstrates that the substrate specificity of the Arg (wild-type) form is unique and that amino acid replacements at position 482 induce major alterations in both the transport activity and substrate specificity of this protein.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2004

Human organic cation transporter 3 mediates the transport of antiarrhythmic drugs.

Antiarrhythmic drugs have been considered to be transported by the organic cation transport system. The purpose of this study was to elucidate the molecular mechanism underlying the transport of antiarrhythmic drugs using cells from the second segment of the proximal tubule (S2) cells of mice expressing human-organic cation transporter 3 (S2 human-OCT3). The antiarrhythmic drugs tested were cibenzoline, disopyramide, lidocaine, mexiletine, phenytoin, pilsicanide, procainamide and quinidine. Human-OCT3 mediated a time- and dose-dependent uptake of quinidine and lidocaine, with Km values of 216 and 139 microM, respectively. Human-OCT3 also mediated the uptake of disopyramide and procainamide but not that of phenytoin. All antiarrhythmic drugs tested inhibited histamine uptake mediated by human-OCT3 in a dose-dependent manner. The IC50 values of antiarrhythmic drugs for human-OCT3 ranged between 0.75 and 656 microM. Kinetic analysis revealed that disopyramide, lidocaine, procainamide and quinidine inhibited histamine uptake mediated by human-OCT3 in a competitive manner. In conclusion, these results suggest that human-OCT3 mediates the transport of antiarrhythmic drugs, which may be the mechanism underlying the distribution and the elimination of these drugs.

Animals↗
PubMed2005

New transport assay demonstrates vesicular acetylcholine transporter has many alternative substrates.

The acetylcholine-binding site in vesicular acetylcholine transporter faces predominantly toward the outside of the vesicle when resting but predominantly toward the inside when transporting. Transport-related reorientation is detected by an ATP-induced decrease in the ability of saturating substrate to displace allosterically bound [(3)H]vesamicol. The assay was used here to determine whether structurally diverse compounds are transported by rat VAChT expressed in PC12(A123.7) cells. Competition by ethidium, tetraphenylphosphonium and other monovalent organic cations with [(3)H]vesamicol is decreased when ATP is added, and the effect depends on proton-motive force. The results indicate that many organic molecules carrying +1 charge are transported, even though the compounds do not resemble acetylcholine in structural details.

Acetylcholine↗
PubMed2006

High-affinity glutamate transporter GLAST/EAAT1 regulates cell surface expression of glutamine/neutral amino acid transporter ASCT2 in human fetal astrocytes.

Neutral amino acid transporter ASCT2, together with high-affinity glutamate transporters, belongs to the SLC1 gene family of Na(+)-dependent solute carriers and is one of the major transporters of glutamine in cultured astrocytes. Besides glutamine and other high-affinity substrates--alanine, serine, cysteine or threonine, ASCT2 can also translocate protonated glutamate. The present study elucidated substrate-dependent trafficking of ASCT2 in differentiated primary cultures of human fetal astrocytes. The differentiation induced by 8-bromo-cAMP caused dramatic up-regulation of two co-localized and functionally linked astroglial proteins--glutamate transporter GLAST, that is the only high-affinity router of glutamate into cultured astrocytes, and glutamine synthetase (GS), a cytosolic enzyme that converts at least a part of the arriving glutamate into glutamine. In order to distinguish individual intracellular effects of these two substrates on ASCT2, in some cultures glutamine synthetase was effectively knocked down using siRNA silencing technique. In control conditions, regardless of GS levels, almost the entire ASCT2 immunoreactivity was restricted to the cytosol. Both glutamine and alanine, though to different extents, induced partial redistribution of ASCT2 from the cytosolic compartment to the plasma membrane. However, in cultures with high GS expression, micromolar concentrations of glutamate exhibited more pronounced effect on ASCT2 trafficking than the preferred substrates of this carrier. In contrast, glutamate had no effect on ASCT2 distribution in cultures devoid of GS. D-Aspartate, a metabolically inert substrate effectively transported by GLAST, had no effect in any cell culture utilized. It seems that intracellular glutamine produced by GS from glutamate that, in turn, is supplied by GLAST, is a more potent inducer of ASCT2 trafficking to the cell surface than the ASCT2-mediated translocation of extracellular substrates. At lower pH values (6.2-6.7), the cell surface pool of ASCT2 was significantly larger than at physiological pH. In addition, high concentrations of glutamate, independently from GLAST or glutamate receptor activation, induced further arrival of ASCT2 to the plasma membrane. The pH-dependent functional activation of ASCT2 and the ASCT2-mediated glutamate uptake may play important roles during ischemic acidosis or synaptic activity-induced local acidification.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2000

Inhibition of glucose transport and direct interactions with type 1 facilitative glucose transporter (GLUT-1) by etomidate, ketamine, and propofol: a comparison with barbiturates.

Ketamine, etomidate, propofol, and pentobarbital were compared for effects on and interactions with the type 1 facilitative glucose transporter (GLUT-1). Fluxes of radiolabeled hexoses were used to determine the effects of anesthetics on GLUT-1 function. Hypotonic hemolysis of human erythrocytes was used to assess perturbations of membrane integrity. Quenching of intrinsic protein fluorescence was used to assess the direct interactions of anesthetics with purified GLUT-1. Pentobarbital, ketamine, etomidate, and propofol inhibited glucose transport in murine fibroblasts with IC(50) values of 0.8, 1. 6, 0.1, and 0.4 mM, respectively. Pentobarbital, ketamine, etomidate, and propofol also inhibited sugar transport in human erythrocytes. The IC(50) values for pentobarbital and ketamine exhibited substrate dependence for equilibrium exchange but not unidirectional effluxes. This was not observed for etomidate. Propofol did not inhibit equilibrium exchange but did inhibit unidirectional efflux with little substrate dependence. Pentobarbital protected against hemolysis, whereas etomidate and ketamine promoted hemolysis of erythrocytes. Propofol had no effect on membrane integrity. Pentobarbital, ketamine, and etomidate all interacted directly with GLUT-1, with apparent K(d) values of 2.2, 0.8, and 0.5 mM, respectively. Like barbiturates, ketamine, etomidate, and propofol inhibited GLUT-1 at concentrations near to those used pharmacologically. Inhibition of GLUT-1 by these intravenous general anesthetics was complex, exhibiting differential kinetic effects on equilibrium exchange versus unidirectional fluxes and contrasting substrate dependencies. Like barbiturates, ketamine and etomidate bound to GLUT-1 with affinities that paralleled inhibition of glucose transport. As a class, intravenous general anesthetics, in contrast to inhalation anesthetics, inhibit GLUT-1-mediated glucose transport.

3T3 Cells↗
PubMed2002

Glutamate/aspartate transporter (GLAST), taurine transporter and metallothionein mRNA levels are differentially altered in astrocytes exposed to manganese chloride, manganese phosphate or manganese sulfate.

Manganese (Mn)-induced neurotoxicity can occur due to environmental exposure (air pollution, soil, water) and/or metabolic aberrations (decreased biliary excretion). High brain manganese levels lead to oxidative stress, as well as alterations in neurotransmitter metabolism with concurrent neurobehavioral deficits. Based on the few existing studies that have examined brain regional Mn concentration, it is likely that in pathological conditions, Mn concentration can reach between 100 and 500 microM. Environmental Mn exposure as a result of methylcyclopentadienyl manganese tricarbonyl (MMT) combustion is in the form of phosphate or sulfate (MnPO4, MnSO4, respectively). Pharmacokinetic studies have shown that the Mn salt will determine the rate of transport into the brain: MnCl2 > MnSO4 > MnPO4. The salt-specific neurotoxicity of these species is unknown. The primary goal of this study was to examine gene expression of glutamate/aspartate transporter (GLAST), taurine transporter (tau-T), and metallothionein-I (MT-I) in astrocytes exposed to manganese chloride (MnCl2), manganese sulfate (MnSO4), and manganese phosphate (MnPO4). We hypothesized that the effects of MnPO4 and MnSO4 exposure on GLASTexpression in astrocytes would be similar to those induced by MnCl2, since irrespective of salt species exposure, once internalized by astrocytes, the Mn ion would be identically complexed. At the same time, we hypothesized that the magnitude of the effect would be salt-dependent, since the chemical speciation would determine the rate of intracellular uptake of Mn. MnCl2 caused a significant overall decrease (P < 0.0001) in astrocytic GLAST mRNA levels with MnSO4 causing a moderate decrease. MnPO4 exposure did not alter GLAST mRNA in astrocytes. We also sought to examine astrocytic metallothionein and taurine transporter gene expression as markers of manganese exposure. Our findings suggest that manganese chloride significantly decreased (P < 0.0001) astrocytic metallothionein mRNA compared to both the sulfate and phosphate species. However, astrocytic taurine transporter mRNA was not affected by Mn exposure, irrespective of the salt species. These data are consistent with the hypothesis that astrocytic neurotoxicity due to Mn exposure is dependent upon its species, with solubility, and by inference, intracellular concentration, representing a major determinant of its neurotoxicity.

Amino Acid Transport System X-AG↗
PubMed1998

MPP+ toxicity and plasma membrane dopamine transporter: study using cell lines expressing the wild-type and mutant rat dopamine transporters.

The Parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium (MPP+) causes specific cell death in dopaminergic neurons after accumulation by the dopamine transporter (DAT). COS cells, a non-neuronal cell line insensitive to high doses of MPP+, becomes sensitive to MPP+ when transfected with the rat DAT cDNA. We analyzed the bi-directional transport of MPP+ and its toxicity in several cell lines expressing wild or mutant DATs. Cell death in COS cells expressing wild DAT by exposure to MPP+ was concentration-dependent and cocaine-reversible. Increased wild DAT expression caused higher sensitivities to the toxin in HeLa cells. Although several mutant DATs demonstrated greater transport activity than the wild-type, they displayed similar or lower sensitivity to MPP+ toxicity. Reverse transport of preloaded [3H]MPP+ through DAT was facilitated in COS cells expressing certain mutant DATs, which consistently displayed less sensitivity to MPP+ toxicity. These results suggest that re-distribution of MPP+ due to influx/efflux turnover through the transporter is a key factor in MPP+ toxicity.

1-Methyl-4-phenylpyridinium↗
PubMed2006

Design and synthesis of promiscuous high-affinity monoamine transporter ligands: unraveling transporter selectivity.

A series of 4-[2-[bis(4-fluorophenyl)methoxy]ethyl]-piperidines and 4-[2-[(bisphenyl)methoxy]ethyl]-piperidines with different types of substituents in the phenylpropyl side-chain were synthesized and examined for their ability to bind to the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET). All of the compounds showed high binding affinities for the DAT in the low to subnanomolar range. Their ability to bind to the SERT and the NET, while maintaining their high affinity for the DAT, could be altered by substitution in positions C2 and C3 of the phenylpropyl side-chain. This approach gave rise to a new set of compounds with selectivity for the DAT, the DAT and the SERT, or the DAT and the NET. Six compounds (7, 9, 11, 12, 14, and 20) with relatively low SERT/DAT ratios were selected for additional study in biogenic amine uptake inhibition assays based on the biogenic amine transporter binding results. Some of the new ligands can serve as pharmacological tools to block DAT or DAT and another transporter simultaneously.

Adrenergic Uptake Inhibitors↗
PubMed2004

Creatinine transport by basolateral organic cation transporter hOCT2 in the human kidney.

PURPOSE: Creatinine is excreted into urine by tubular secretion in addition to glomerular filtration. The purpose of this study was to clarify molecular mechanisms underlying the tubular secretion of creatinine in the human kidney. METHODS: Transport of [14C]creatinine by human organic ion transporters (SLC22A) was assessed by HEK293 cells expressing hOCT1, hOCT2, hOCT2-A, hOAT1, and hOAT3. RESULTS: Among the organic ion transporters examined, only hOCT2 stimulated creatinine uptake when expressed in HEK293 cells. Creatinine uptake by hOCT2 was dependent on the membrane potential. The Michaelis constant (Km) for creatinine transport by hOCT2 was 4.0 mM, suggesting low affinity. Various cationic drugs including cimetidine and trimethoprim, but not anionic drugs, markedly inhibited creatinine uptake by hOCT2. CONCLUSION: These results suggest that hOCT2, but not hOCT1, is responsible for the basolateral membrane transport of creatinine in the human kidney.

1-Methyl-4-phenylpyridinium↗