Research & Teaching Faculty

Polyamine Transport by the Polyspecific Organic Cation Transporters OCT1, OCT2, and OCT3

TitlePolyamine Transport by the Polyspecific Organic Cation Transporters OCT1, OCT2, and OCT3
Publication TypeJournal Article
Year of Publication2013
AuthorsSala-Rabanal, M, Li, DC, Dake, GR, Kurata, HT, Inyushin, M, Skatchkov, SN, Nichols, CG
Date PublishedAPR

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, {[}H-3]MPP+ uptake rates were 15- to 35-fold higher than in noninjected oocytes, whereas those for {[}H-3]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 similar to 50 mu M in OCT1, similar to 170 mu M in OCT2, and similar to 60 mu M in OCT3, whereas for spermidine, K-0.5 was similar to 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 {[}H-3]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.