Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Polyamine transport by the polyspecific organic cation transporters OCT1, OCT2, and OCT3.
Sala-Rabanal M
,
Li DC
,
Dake GR
,
Kurata HT
,
Inyushin M
,
Skatchkov SN
,
Nichols CG
.
???displayArticle.abstract???
Polyamines are ubiquitous organic cations implicated in many physiological processes. Because they are positively charged at physiological pH, carrier-mediated systems are necessary for effective membrane permeation, but the identity of specific polyamine transporter proteins in eukaryotic cells remains unclear. Polyspecific organic cation transporters (OCTs) interact with many natural and xenobiotic monovalent cations and have been reported to transport dicationic compounds, including the short polyamine putrescine. In this study, we used Xenopus oocytes expressing mammalian OCT1 (SLC22A1), OCT2 (SLC22A2), or OCT3 (SLC22A3) to assess binding and transport of longer-chain polyvalent polyamines. In OCT-expressing oocytes, [(3)H]MPP(+) uptake rates were 15- to 35-fold higher than in noninjected oocytes, whereas those for [(3)H]spermidine increased more modestly above the background, up to 3-fold. This reflected up to 20-fold lower affinity for spermidine than for MPP(+); thus, K(0.5) for MPP(+) was ~50 μM in OCT1, ~170 μM in OCT2, and ~60 μM in OCT3, whereas for spermidine, K(0.5) was ~1 mM in OCT1, OCT2, and OCT3. J(max) values for MPP(+) and spermidine were within the same range, suggesting that both compounds are transported at a similar turnover rate. To gain further insight into OCT substrate specificity, we screened a selection of structural polyamine analogues for effect on [(3)H]MPP(+) uptake. In general, blocking potency increased with overall hydrophobic character, which indicates that, as for monovalent cations, hydrophobicity is a major requirement for recognition in polyvalent OCT substrates and inhibitors. Our results demonstrate that the natural polyamines are low affinity, but relatively high turnover, substrates for OCTs. The identification of OCTs as polyamine transport systems may contribute to further understanding of the mechanisms involved in polyamine homeostasis and aid in the design of polyamine-like OCT-targeted drugs.
Abramson,
Structure and mechanism of the lactose permease of Escherichia coli.
2003, Pubmed
Abramson,
Structure and mechanism of the lactose permease of Escherichia coli.
2003,
Pubmed
Ahlin,
Structural requirements for drug inhibition of the liver specific human organic cation transport protein 1.
2008,
Pubmed
Aouida,
AGP2 encodes the major permease for high affinity polyamine import in Saccharomyces cerevisiae.
2005,
Pubmed
Bednarczyk,
Influence of molecular structure on substrate binding to the human organic cation transporter, hOCT1.
2003,
Pubmed
Benedikt,
Intracellular polyamines enhance astrocytic coupling.
2012,
Pubmed
Bockenhauer,
Epilepsy, ataxia, sensorineural deafness, tubulopathy, and KCNJ10 mutations.
2009,
Pubmed
,
Xenbase
Burckhardt,
Effect of primary, secondary and tertiary amines on membrane potential and intracellular pH in Xenopus laevis oocytes.
1995,
Pubmed
,
Xenbase
Busch,
Monoamine neurotransmitter transport mediated by the polyspecific cation transporter rOCT1.
1996,
Pubmed
,
Xenbase
Busch,
Electrogenic properties and substrate specificity of the polyspecific rat cation transporter rOCT1.
1996,
Pubmed
,
Xenbase
Busch,
Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine.
1998,
Pubmed
,
Xenbase
Casero,
Polyamine catabolism and disease.
2009,
Pubmed
Casero,
Targeting polyamine metabolism and function in cancer and other hyperproliferative diseases.
2007,
Pubmed
Chen,
Transport of paraquat by human organic cation transporters and multidrug and toxic compound extrusion family.
2007,
Pubmed
Choi,
Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences.
2008,
Pubmed
Ciarimboli,
Role of organic cation transporters in drug-induced toxicity.
2011,
Pubmed
Cui,
The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway.
2009,
Pubmed
Dresser,
Kinetic and selectivity differences between rodent, rabbit, and human organic cation transporters (OCT1).
2000,
Pubmed
,
Xenbase
Enkvetchakul,
Polyamine flux in Xenopus oocytes through hemi-gap junctional channels.
2003,
Pubmed
,
Xenbase
Gorboulev,
Selectivity of the polyspecific cation transporter rOCT1 is changed by mutation of aspartate 475 to glutamate.
1999,
Pubmed
,
Xenbase
Gorboulev,
Cloning and characterization of two human polyspecific organic cation transporters.
1997,
Pubmed
,
Xenbase
Gorboulev,
Subtype-specific affinity for corticosterone of rat organic cation transporters rOCT1 and rOCT2 depends on three amino acids within the substrate binding region.
2005,
Pubmed
,
Xenbase
Gorbunov,
High-affinity cation binding to organic cation transporter 1 induces movement of helix 11 and blocks transport after mutations in a modeled interaction domain between two helices.
2008,
Pubmed
Gründemann,
Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2).
2003,
Pubmed
Harlfinger,
Are organic cation transporters capable of transporting prostaglandins?
2005,
Pubmed
Hibino,
Inwardly rectifying potassium channels: their structure, function, and physiological roles.
2010,
Pubmed
Hosoya,
Roles of organic anion/cation transporters at the blood-brain and blood-cerebrospinal fluid barriers involving uremic toxins.
2011,
Pubmed
Huang,
Structure and mechanism of the glycerol-3-phosphate transporter from Escherichia coli.
2003,
Pubmed
Igarashi,
Modulation of cellular function by polyamines.
2010,
Pubmed
Inazu,
Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes.
2003,
Pubmed
Inyushin,
Potassium channel activity and glutamate uptake are impaired in astrocytes of seizure-susceptible DBA/2 mice.
2010,
Pubmed
Isome,
The antiproliferative effects of agmatine correlate with the rate of cellular proliferation.
2007,
Pubmed
Koepsell,
Substrate recognition and translocation by polyspecific organic cation transporters.
2011,
Pubmed
Koepsell,
Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications.
2007,
Pubmed
Kucheryavykh,
Complex rectification of Müller cell Kir currents.
2008,
Pubmed
Lin,
Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP transport across the blood-brain barrier and MPTP-induced dopaminergic toxicity in rodents.
2010,
Pubmed
Lips,
Polyspecific cation transporters mediate luminal release of acetylcholine from bronchial epithelium.
2005,
Pubmed
,
Xenbase
Loussouarn,
Molecular basis of inward rectification: structural features of the blocker defined by extended polyamine analogs.
2005,
Pubmed
Ming,
Transport of dicationic drugs pentamidine and furamidine by human organic cation transporters.
2009,
Pubmed
Müller,
Drug specificity and intestinal membrane localization of human organic cation transporters (OCT).
2005,
Pubmed
Nichols,
Inward rectifier potassium channels.
1997,
Pubmed
Nies,
Organic cation transporters (OCTs, MATEs), in vitro and in vivo evidence for the importance in drug therapy.
2011,
Pubmed
Nishimura,
Tissue-specific mRNA expression profiles of human ATP-binding cassette and solute carrier transporter superfamilies.
2005,
Pubmed
Pegg,
Mammalian polyamine metabolism and function.
2009,
Pubmed
Popp,
Amino acids critical for substrate affinity of rat organic cation transporter 1 line the substrate binding region in a model derived from the tertiary structure of lactose permease.
2005,
Pubmed
,
Xenbase
Poulin,
Recent advances in the molecular biology of metazoan polyamine transport.
2012,
Pubmed
Rock,
Polyamine regulation of N-methyl-D-aspartate receptor channels.
1995,
Pubmed
Sala-Rabanal,
Molecular mechanisms of EAST/SeSAME syndrome mutations in Kir4.1 (KCNJ10).
2010,
Pubmed
Sata,
Functional analysis of organic cation transporter 3 expressed in human placenta.
2005,
Pubmed
Scholl,
Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10.
2009,
Pubmed
Sha,
Spermidine release from xenopus oocytes. Electrodiffusion through a membrane channel.
1996,
Pubmed
,
Xenbase
Sobczak,
Endogenous transport systems in the Xenopus laevis oocyte plasma membrane.
2010,
Pubmed
,
Xenbase
Suhre,
Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters hOCT2 and rbOCT2.
2005,
Pubmed
Uemura,
Identification and characterization of a diamine exporter in colon epithelial cells.
2008,
Pubmed
Van Dobbenburgh,
Plasma spermidine concentrations as early indication of response to therapy in human myeloma.
1983,
Pubmed
Wang,
Inhibitory effect of agmatine on proliferation of tumor cells by modulation of polyamine metabolism.
2005,
Pubmed
Weiger,
External action of di- and polyamines on maxi calcium-activated potassium channels: an electrophysiological and molecular modeling study.
1998,
Pubmed
Winter,
OCT2 and MATE1 provide bidirectional agmatine transport.
2011,
Pubmed
Wright,
Molecular and cellular physiology of renal organic cation and anion transport.
2004,
Pubmed
Wright,
Role of organic cation transporters in the renal handling of therapeutic agents and xenobiotics.
2005,
Pubmed
Zhang,
The interaction of n-tetraalkylammonium compounds with a human organic cation transporter, hOCT1.
1999,
Pubmed
Zhang,
A conserved glutamate residue in transmembrane helix 10 influences substrate specificity of rabbit OCT2 (SLC22A2).
2005,
Pubmed
Zolk,
Structural determinants of inhibitor interaction with the human organic cation transporter OCT2 (SLC22A2).
2009,
Pubmed
Zolk,
Disposition of metformin: variability due to polymorphisms of organic cation transporters.
2012,
Pubmed
