Agmatine is efficiently transported by non-neuronal monoamine transporters extraneuronal monoamine transporter (EMT) and organic cation transporter 2 (OCT2)

被引:80
作者
Gründemann, DG [1 ]
Hahne, C [1 ]
Berkels, R [1 ]
Schömig, E [1 ]
机构
[1] Univ Cologne, Dept Pharmacol, D-50931 Cologne, Germany
关键词
D O I
10.1124/jpet.102.044404
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Agmatine has received considerable attention recently. Available evidence suggests that agmatine functions as a neurotransmitter and inhibits, via induction of antizyme, cellular proliferation. Because of its positive charge, agmatine will not appreciably cross cellular membranes by simple diffusion. Indeed, all physiological models require a channel or transporter protein in the plasma membrane to effect inactivation or non-exocytotic release of agmatine. However, a transport mechanism for agmatine has not been identified on a molecular level so far. In the present study, the non-neuronal monoamine transporters, organic cation transporter (OCT) 1, OCT2, and extraneuronal monoamine transporter (EMT) (gene symbols SLC22A1-A3), both from human and rat, were examined, stably expressed in 293 cells, for [H-3] agmatine transport. Our results indicate that OCT2 and EMT, but not OCT1, efficiently translocate agmatine. The structural homolog putrescine was not accepted as substrate. Uptake of agmatine via EMT and OCT2 was saturable, with K-m values of 1 to 2 mM. The affinity of OCT1 was 10-fold lower. Carrier-mediated efflux of agmatine was documented in a trans-stimulation experiment. Finally, uptake of agmatine increased dramatically with increasing pH. Thus, only the singly charged species of agmatine is accepted as substrate. In conclusion, both EMT and OCT2 must be considered for the control of agmatine levels in rat and human.
引用
收藏
页码:810 / 817
页数:8
相关论文
共 33 条
[1]  
Babál P, 2001, J PHARMACOL EXP THER, V296, P372
[2]   Catecholamine transport by the organic cation transporter type 1 (OCT1) [J].
Breidert, T ;
Spitzenberger, F ;
Gründemann, D ;
Schömig, E .
BRITISH JOURNAL OF PHARMACOLOGY, 1998, 125 (01) :218-224
[3]   Human neurons express the polyspecific cation transporter hOCT2, which translocates monoamine neurotransmitters, amantadine, and memantine [J].
Busch, AE ;
Karbach, U ;
Miska, D ;
Gorboulev, V ;
Akhoundova, A ;
Volk, C ;
Arndt, P ;
Ulzheimer, JC ;
Sonders, MS ;
Baumann, C ;
Waldegger, S ;
Lang, F ;
Koepsell, H .
MOLECULAR PHARMACOLOGY, 1998, 54 (02) :342-352
[4]   Transport and metabolism of agmatine in rat hepatocyte cultures [J].
Cabella, C ;
Gardini, G ;
Corpillo, D ;
Testore, G ;
Bedino, S ;
Solinas, SP ;
Cravanzola, C ;
Vargiu, C ;
Grillo, MA ;
Colombatto, S .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 2001, 268 (04) :940-947
[5]   Agmatine uptake by cultured hamster kidney cells [J].
del Valle, AE ;
Paz, JC ;
Sánchez-Jiménez, F ;
Medina, MA .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2001, 280 (01) :307-311
[6]   Cloning and characterization of two human polyspecific organic cation transporters [J].
Gorboulev, V ;
Ulzheimer, JC ;
Akhoundova, A ;
UlzheimerTeuber, I ;
Karbach, U ;
Quester, S ;
Baumann, C ;
Lang, F ;
Busch, AE ;
Koepsell, H .
DNA AND CELL BIOLOGY, 1997, 16 (07) :871-881
[7]   Transport of monoamine transmitters by the organic cation transporter type 2, OCT2 [J].
Gründemann, D ;
Köster, S ;
Kiefer, N ;
Breidert, T ;
Engelhardt, M ;
Spitzenberger, F ;
Obermüller, N ;
Schömig, E .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (47) :30915-30920
[8]   Activation of the extraneuronal monoamine transporter (EMT) from rat expressed in 293 cells [J].
Gründemann, D ;
Koschker, AC ;
Haag, C ;
Honold, C ;
Zimmermann, T ;
Schömig, E .
BRITISH JOURNAL OF PHARMACOLOGY, 2002, 137 (06) :910-918
[9]  
Grundemann D, 1997, J BIOL CHEM, V272, P10408
[10]   Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter [J].
Grundemann, D ;
Schechinger, B ;
Rappold, GA ;
Schomig, E .
NATURE NEUROSCIENCE, 1998, 1 (05) :349-351