OCT2 and MATE1 provide bidirectional agmatine transport.
Agmatine is a biogenic amine (l-arginine metabolite) of potential relevance to several central nervous system (CNS) conditions. The identities of transporters underlying agmatine and polyamine disposition in mammalian systems are not well-defined. The SLC-family organic cation transporters (OCT) OCT1 and OCT2 and multidrug and toxin extrusion transporter-1 (MATE1) are transport systems that may be of importance for the cellular disposition of agmatine and putrescine. We investigated the transport of [(3)H]agmatine and [(3)H]putrescine in human embryonic kidney (HEK293) cells stably transfected with hOCT1, hOCT2, and hMATE1. Agmatine transport by hOCT1 and hOCT2 was concentration-dependent, whereas only hOCT2 demonstrated pH-dependent transport. hOCT2 exhibited a greater affinity for agmatine (K(m) = 1.84 ± 0.38 mM) than did hOCT1 (K(m) = 18.73 ± 4.86 mM). Putrescine accumulation was pH- and concentration-dependent in hOCT2-HEK cells (K(m) = 11.29 ± 4.26 mM) but not hOCT1-HEK cells. Agmatine accumulation, in contrast to putrescine, was significantly enhanced by hMATE1 overexpression, and was saturable (K(m) = 240 ± 31 μM; V(max) = 192 ± 10 pmol/min/mg of protein). Intracellular agmatine was also trans-stimulated (effluxed) from hMATE1-HEK cells in the presence of an inward proton-gradient. The hMATE1-mediated transport of agmatine was inhibited by polyamines, the prototypical substrates MPP+ and paraquat, as well as guanidine and arcaine, but not l-arginine. These results suggest that agmatine disposition may be influenced by hOCT2 and hMATE1, two transporters critical in the renal elimination of xenobiotic compounds.
Departments of Pharmaceutics, Pharmacology, and Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Tate N
TN
Winter
William F
WF
Elmquist
Carolyn A
CA
Fairbanks
D000376:Agmatine / Q000378:metabolism*; D001692:Biological Transport / Q000235:genetics / Q000502:physiology; D002460:Cell Line; D006801:Humans; D006863:Hydrogen-Ion Concentration; D027701:Organic Cation Transport Proteins / Q000235:genetics / Q000378:metabolism*; D027702:Organic Cation Transporter 1 / Q000235:genetics / Q000378:metabolism; D000075102:Organic Cation Transporter 2; D011700:Putrescine / Q000378:metabolism
D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D000075102:Organic Cation Transporter 2; C491013:SLC22A2 protein, human; C521869:SLC47A1 protein, human; D000376:Agmatine; D011700:Putrescine