Transport of Monoamine Transmitters by the Organic Cation Transporter Type 2, OCT2

Gründemann, Dirk; Köster, Sandra; Kiefer, Nicholas; Breidert, Tilo; Engelhardt, Martin; Spitzenberger, Folker; Obermüller, Nicholas; Schömig, Edgar

doi:10.1074/jbc.273.47.30915

Cited by 145 publications

(92 citation statements)

References 23 publications

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“…However, although Oct1 and Oct2 have similar substrate specificities, they are not identical (31,32), and a deficiency in either Oct1 or Oct2 may already be sufficient to impair the renal secretion of some substrates. Moreover, in contrast to rodents, which express both Oct1 and Oct2 in the kidney, humans only express OCT2 (10). Therefore, a deficiency in OCT2 in humans might have effects on renal elimination similar to those of a deficiency in both Oct1 and Oct2 in mice.…”

Section: Discussionmentioning

confidence: 99%

“…The latter is exemplified by the antidiabetic drug metformin, which has been shown to have reduced toxicity in Oct1 Ϫ/Ϫ mice (33,34). Unlike rodents that express both Oct1 and Oct2 in the kidney, humans express only OCT2 (10). Therefore, it is likely that the Oct1/2 Ϫ/Ϫ mouse model better reflects the effect on renal function of an OCT2 deficiency in humans than the Oct2 Ϫ/Ϫ mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…Oct2 (Slc22a2) has a substrate specificity similar to that of Oct1 but is predominantly expressed in the kidney in both rodents and humans (10).…”

mentioning

confidence: 99%

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Deficiency in the Organic Cation Transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in Mice Abolishes Renal Secretion of Organic Cations

Jonker

Wagenaar

Eijl

et al. 2003

Molecular and Cellular Biology

243

164

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The polyspecific organic cation transporters 1 and 2 (Oct1 and -2) transport a broad range of substrates, including drugs, toxins, and endogenous compounds. Their strategic localization in the basolateral membrane of epithelial cells in the liver, intestine (Oct1), and kidney (Oct1 and Oct2) suggests that they play an essential role in removing noxious compounds from the body. We previously showed that in Oct1 ؊/؊ mice, the hepatic uptake and intestinal excretion of organic cations are greatly reduced. Since Oct1 and Oct2 have extensively overlapping substrate specificities, they might be functionally redundant. To investigate the pharmacologic and physiologic roles of these proteins, we generated Oct2 single-knockout and Oct1/2 double-knockout mice. Oct2؊/؊ and Oct1/2 ؊/؊ mice are viable and fertile and display no obvious phenotypic abnormalities. Absence of Oct2 in itself had little effect on the pharmacokinetics of tetraethylammonium (TEA), but in Oct1/2 ؊/؊ mice, renal secretion of this compound was completely abolished, leaving only glomerular filtration as a TEA clearance mechanism. As a consequence, levels of TEA were substantially increased in the plasma of Oct1/2 ؊/؊ mice. This study shows that Oct1 and Oct2 together are essential for renal secretion of (small) organic cations. A deficiency in these proteins may thus result in increased drug sensitivity and toxicity.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Deficiency in the Organic Cation Transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in Mice Abolishes Renal Secretion of Organic Cations

Jonker

Wagenaar

Eijl

et al. 2003

Molecular and Cellular Biology

243

164

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“…10) H] spermine uptake was not significantly changed by 0.1 mM decynium-22, which is an inhibitor of PMAT and OCT1-3, and 1 mM tetraethylammonium (TEA), a substrate of OCTN1-2, OCT1-3, and MATE1-2. [29][30][31][32] From this inhibition study using the rat choroid plexus, it appears that spermine transport at the apical membrane of BCSFB involves polyamine-and several cationic compound-recognizing transporters, but not OCT1-3, OCTN1-2, MATE1-2, and PMAT.…”

Section: Resultsmentioning

confidence: 99%

Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Akanuma

Shimada

Kubo

et al. 2017

Biological & Pharmaceutical Bulletin

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Spermine is the end-product in the polyamine biosynthetic pathway, and its excess accumulation induces neuroexcitatory responses and neurotoxicity. The purpose of this study was to elucidate the involvement of transport systems at the brain barriers in the clearance of spermine. In vivo rat spermine elimination from brain parenchyma across the blood-brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (BCSFB) was assessed by intracerebral and intracerebroventricular administration techniques, respectively. To characterize spermine transport at the BCSFB, a transport study using rat choroid plexus was performed. After the intracerebral microinjection of [ Spermine is a natural polyamine, and the end-product in the polyamine biosynthetic pathway.1) In the brain, spermine binds to N-methyl-D-aspartate receptors, and is involved in the modulation of learning and memory.2,3) In addition, excess accumulation of spermine induces neuroexcitatory responses and, thus, neurotoxicity. 4) Therefore, it is considered that some mechanisms for control of the cerebral spermine concentration are present in the brain to maintain homeostasis of cerebral function via spermine-related neuro-responses. The precursor of spermine is spermidine, 5) which is synthesized from putrescine and it has been reported that the biosynthesis of spermine from spermidine is superior to that of spermidine from spermine.6-8) Hence, neural spermine transport system(s) could be important for the removal of spermine from the brain, and the modulation of cerebral spermine concentration.Brain parenchyma and cerebrospinal fluid (CSF) are separated from the circulating blood by the blood-brain barrier (BBB) and blood-CSF barrier (BCSFB), respectively. The BBB and BCSFB are formed by brain capillary endothelial and choroid plexus epithelial cells, respectively, and express some transporting molecules which are involved in active elimination of compound from the brain or CSF.9) Regarding the cationic compound elimination system(s) at these barriers, mRNAs of plasma membrane monoamine transporter (PMAT/ solute carrier (SLC)29A4), organic cation/carnitine transporter 1-2 (OCTN1-2/SLC22A4-5), organic cation transporter 1-3 (OCT1-3/SLC22A1-3), and multidrug and toxin extrusion 1-2 (MATE1-2/SLC47A1-2) are expressed in rat BBB and BCSFB cell lines. 10) Among these transporters, PMAT is, at least in part, involved in brain/CSF-to-blood transport of 1-methyl-4-phenylpyridinium (MPP + ) 10) and CSF-to-blood transport of histamine.11) In addition, OCT3 takes part in the efflux transport of creatinine, a cationic guanidino compound.12) Therefore, it is possible that cerebral spermine is eliminated across these brain barriers.Some previous studies have reported that polyamines including spermine are transported in a carrier-mediated manner in some organs and it has been reported that carrier-mediated transport of polyamines is present in mammalian intestine, liver, and kidney. [13][14][15] In addition, we have demonstrated that the rat inner blood-retinal barr...

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“…Based on studies of peripheral tissues, all three OCTs transport 5-HT, dopamine, and norepinephrine (Busch et al, 1996;Grundemann et al, 1998;Koepsell et al, 2003) and are acutely inhibited by corticosterone (Wu et al, 1998;Arndt et al, 2001). OCT expression has been detected in neurons and cultured glial cells (Russ et al, 1996;Busch et al, 1998;Vialou et al, 2004), and physiological roles for OCTs in the brain have been suggested (Kristufek et al, 2002;Kitaichi et al, 2003;Vialou et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Corticosterone-Sensitive Monoamine Transport in the Rat Dorsomedial Hypothalamus: Potential Role for Organic Cation Transporter 3 in Stress-Induced Modulation of Monoaminergic Neurotransmission

Gasser¹,

Lowry²,

Orchinik³

2006

J. Neurosci.

127

104

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Transport of Monoamine Transmitters by the Organic Cation Transporter Type 2, OCT2

Abstract: The recently cloned apical renal transport system for organic cations (OCT2) exists in dopamine-rich tissues such as kidney and some brain areas (Grü ndemann, D., Babin-Ebell, J., Martel, F., Ö rding, N., Schmidt, A., and Schö mig, E.

Cited by 145 publications

References 23 publications

Deficiency in the Organic Cation Transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in Mice Abolishes Renal Secretion of Organic Cations

Deficiency in the Organic Cation Transporters 1 and 2 (Oct1/Oct2 [Slc22a1/Slc22a2]) in Mice Abolishes Renal Secretion of Organic Cations

Involvement of Carrier-Mediated Transport at the Blood–Cerebrospinal Fluid Barrier in Spermine Clearance from Rat Brain

Corticosterone-Sensitive Monoamine Transport in the Rat Dorsomedial Hypothalamus: Potential Role for Organic Cation Transporter 3 in Stress-Induced Modulation of Monoaminergic Neurotransmission

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