Functional characterization of Rat Plasma Membrane Monoamine Transporter in the Blood–Brain and Blood–Cerebrospinal Fluid Barriers

Okura, Takashi; Kato, Sayaka; Takano, Yusuke; Sato, Takenori; Yamashita, Atsushi; Morimoto, Riyo; Ohtsuki, Sumio; Terasaki, Tetsuya; Deguchi, Yoshiaki

doi:10.1002/jps.22594

Cited by 42 publications

(69 citation statements)

References 44 publications

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“…Few in vivo studies have investigated the presence and role of biogenic amines transporters in clearance and dissipation at the abluminal BBB. Pmat could be involved in the clearance and dissipation of dopamine and serotonin at the abluminal/nervous side of the BBB in addition to its role in their neuronal transport (Dahlin et al, 2007;Duan and Wang, 2010;Okura et al, 2011). But, we could not show either Oct3 or Pmat in endothelial cells by immunostaining or luminal transport experiments.…”

Section: Discussioncontrasting

confidence: 56%

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

André

Saubaméa

Cochois-Guégan

et al. 2012

J Cereb Blood Flow Metab

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Uptake1 and uptake2 transporters are involved in the extracellular clearance of biogenic amine neurotransmitters at synaptic clefts. We looked for them at the blood-brain barrier (BBB) and bloodretina barriers (BRB), where they could be involved in regulating the neurotransmitter concentration and modulate/terminate receptor-mediated effects within the neurovascular unit (NVU). Uptake2 (Oct1-3/ Slc22a1-3, Pmat/Slc29a4) and Mate1/Slc47a1 transporters are also involved in the transport of xenobiotics. We used in situ carotid perfusion of prototypic substrates like-serotonin, and [ 3 H]-dopamine, changes in ionic composition and genetic deletion of Oct1-3 carriers to detect uptake1 and uptake2 at the BBB and BRB. We showed that uptake1 and uptake2 are involved in the transport of [ 3 H]-dopamine and [ 3 H]-MPP + at the blood luminal BRB, but not at the BBB. These functional studies, together with quantitative RT-PCR and confocal imaging, suggest that the mouse BBB lacks uptake1 (Net/Slc6a2, Dat/Slc6a3, Sert/Slc6a4), uptake2, and Mate1 on both the luminal and abluminal sides. However, we found evidence for functional Net and Oct1 transporters at the luminal BRB. These heterogeneous transport properties of the brain and retina NVUs suggest that the BBB helps protect the brain against biogenic amine neurotransmitters in the plasma while the BRB has more of a metabolic/endocrine role.

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Section: Discussioncontrasting

confidence: 56%

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

André

Saubaméa

Cochois-Guégan

et al. 2012

J Cereb Blood Flow Metab

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“…Apart from OCT3, it has been reported that OCTN1-2, MATE1-2, and PMAT mRNAs are expressed in a cell line of rat choroid plexus epithelial cells. 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%

“…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.…”

mentioning

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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“…We also showed that PMAT mRNA and protein are highly expressed in choroid plexus, which constitutes the blood-cerebrospinal fluid barrier (Dahlin et al, 2007(Dahlin et al, , 2009. Recent brain microdialysis studies in rats further support a role of PMAT in brain-to-blood transport of OCs such as monoamines and cationic neurotoxins (Okura et al, 2011). Given the biological and pharmacological significance of PMAT, it is important to understand the transport mechanism of PMAT and identify physiological and pathological factors and/or conditions that may exert modulatory roles on PMAT activity toward OCs.…”

Section: Introductionmentioning

confidence: 83%

“…PMAT is a polyspecific OC transporter recently implicated in the disposition of organic cations in the intestine and brain (Zhou et al, 2007b;Okura et al, 2011). The goal of this study was to elucidate the electrophysiological characteristics of PMAT, focusing on the role of membrane potential and physiological ion gradients on PMAT-mediated OC transport.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Characterization of the Polyspecific Organic Cation Transporter Plasma Membrane Monoamine Transporter

Itagaki

Ganapathy

et al. 2012

Drug Metab Dispos

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ABSTRACT:Plasma membrane monoamine transporter (PMAT) is a polyspecific organic cation (OC) transporter that transports a variety of endogenous biogenic amines and xenobiotic cations. Previous radiotracer uptake studies showed that PMAT-mediated OC transport is sensitive to changes in membrane potential and extracellular pH, but the precise role of membrane potential and protons on PMAT-mediated OC transport is unknown. Here, we characterized the electrophysiological properties of PMAT in Xenopus laevis oocytes using a two-microelectrode voltage-clamp approach. PMAT-mediated histamine uptake is associated with inward currents under voltage-clamp conditions, and the currents increased in magnitude as the holding membrane potential became more negative. A similar effect was also observed for another cation, nicotine. Substrate-induced currents were largely independent of Na ؉ but showed strong dependence on membrane potential and pH of the perfusate. Detailed kinetic analysis of histamine uptake revealed that the energizing effect of membrane potentials on PMAT transport is mainly due to an augmentation of I max with little effect on K 0.5 . At most holding membrane potentials, I max at pH 6.0 is approximately 3-to 4-fold higher than that at pH 7.5, whereas K 0.5 is not dependent on pH. Together, these data unequivocally demonstrate PMAT as an electrogenic transporter and establish the physiological inside-negative membrane potential as a driving force for PMAT-mediated OC transport. The important role of membrane potential and pH in modulating the transport activity of PMAT toward OCs suggests that the in vivo activity of PMAT could be regulated by pathophysiological processes that alter physiological pH or membrane potential.

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Functional characterization of Rat Plasma Membrane Monoamine Transporter in the Blood–Brain and Blood–Cerebrospinal Fluid Barriers

Cited by 42 publications

References 44 publications

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

Transport of Biogenic Amine Neurotransmitters at the Mouse Blood–Retina and Blood–Brain Barriers by Uptake1 and Uptake2

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

Electrophysiological Characterization of the Polyspecific Organic Cation Transporter Plasma Membrane Monoamine Transporter

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