Expression of the extraneuronal monoamine transporter (uptake2) in human glioma cells

Streich, Sabine; Brüss, Michael; Bönisch, Heinz

doi:10.1007/bf00168636

Cited by 45 publications

(37 citation statements)

References 36 publications

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“…Moreover, under our conditions, brain astrocytes did not express detectable levels of OCT3. This contradicts previous reports of the presence of Uptake 2 and OCTs in human glioma cells and cultured rat astrocytes Streich et al, 1996;Schomig et al, 1998;Hayer-Zillgen et al, 2002). These previous results led to the assumption that in vivo, in normal brain OCTs are located in astrocytes, which is not the case, as shown here.…”

Section: Discussioncontrasting

confidence: 99%

Organic Cation Transporter 3 (Slc22a3) Is Implicated in Salt-Intake Regulation

Vialou¹,

Amphoux²,

Zwart³

et al. 2004

J. Neurosci.

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Organic cation transporters (OCTs) are carrier-type permeases known to participate in general detoxification functions in peripheral tissues. Previous in vitro studies have suggested that OCTs ensure Uptake 2 , a low-affinity, corticosteroid-sensitive catecholamine removal system, which was characterized initially in sympathetically innervated tissues. Although the presence of both Uptake 2 -like transport and most OCT subtypes has also been demonstrated in the brain, the physiological role of this family of transporters in CNS remained totally unknown. In the present work, we show that the OCT3 transporter is found throughout the brain and highly expressed in regions regulating fluid exchange, including circumventricular organs such as area postrema and subfornical organ (SFO), and in other structures implicated in the sensing of changes in blood osmolarity and regulation of salt and water ingestion. OCT3/Slc22a3-deficient mice show an increase in the level of ingestion of hypertonic saline under thirst and salt appetite conditions, as well as alterations of the neural response in the SFO after sodium deprivation, as monitored by Fos immunoreactivity. This work demonstrates that the presence of OCT3 is critical for the balanced neural and behavioral responses to environmentally induced variations in osmolarity and provides for the first time physiological evidence of the importance of OCTs for CNS function.

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Section: Discussioncontrasting

confidence: 99%

Organic Cation Transporter 3 (Slc22a3) Is Implicated in Salt-Intake Regulation

Vialou¹,

Amphoux²,

Zwart³

et al. 2004

J. Neurosci.

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“…Most of the functional studies involving this transporter have been done in peripheral tissues. However, recent studies have provided evidence for the expression of the extraneuronal monoamine transporter in the central nervous system (43)(44)(45)(46). The present study demonstrating the widespread expression of OCT3 in the brain corroborates these findings.…”

Section: Discussionsupporting

confidence: 82%

Identity of the Organic Cation Transporter OCT3 as the Extraneuronal Monoamine Transporter (uptake2) and Evidence for the Expression of the Transporter in the Brain

Wu¹,

Kekuda²,

Huang³

et al. 1998

Journal of Biological Chemistry

344

303

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We investigated the transport of cationic neurotoxins and neurotransmitters by the potential-sensitive organic transporter OCT3 and its steroid sensitivity using heterologous expression systems and also analyzed the expression of OCT3 in the brain. When expressed in mammalian cells, OCT3 mediates the uptake of the neurotoxin 1-methyl-4-phenylpyridinium (MPP ؉ ) and the neurotransmitter dopamine. Competition experiments show that several cationic neuroactive agents including amphetamines interact with OCT3. When expressed in Xenopus laevis oocytes, OCT3-mediated MPP ؉ uptake is associated with inward currents under voltage-clamp conditions. The MPP ؉ -induced currents are saturable with respect to MPP ؉ concentration, and half-maximal saturation (K 0.5 ) occurs at about 25 M MPP ؉ with membrane potential clamped at ؊50 mV. The K 0.5 for MPP ؉ is markedly influenced by membrane potential. OCT3 is inhibited by several steroids, and ␤-estradiol is the most potent inhibitor (K i ϳ1 M). The pattern of steroid sensitivity of OCT3 is different from that of OCT1 and OCT2 but correlates significantly with that of the extraneuronal monoamine transporter (uptake 2 ). The transport characteristics and steroid sensitivity provide strong evidence for the molecular identity of OCT3 as uptake 2 . OCT3 is expressed in the brain as evidenced from Northern blot analysis, reverse transcription-polymerase chain reaction, and in situ hybridization using OCT3-specific probes. The molecular identity of the transcript hybridizing to the probe has been established by sequencing the reverse transcription-polymerase chain reaction product and also by the isolation of the OCT3 cDNA from a brain cDNA library. Regional distribution studies with in situ hybridization show that OCT3 is expressed widely in different brain regions, especially in the hippocampus, cerebellum, and cerebral cortex. OCT3 is likely to play a significant role in the disposition of cationic neurotoxins and neurotransmitters in the brain.

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“…It was concluded that EMT, among others, is not responsible for agmatine uptake into SK-MG-1 cells. This is difficult to reconcile with our data, however, since EMT is functionally expressed in this cell line (Streich et al, 1996). Thus, although the available data suggest that in SK-MG-1 cells, a transporter other than EMT or OCT2 is responsible for agmatine uptake, some additional verification is desirable.…”

Section: Discussioncontrasting

confidence: 57%

Agmatine Is Efficiently Transported by Non-Neuronal Monoamine Transporters Extraneuronal Monoamine Transporter (EMT) and Organic Cation Transporter 2 (OCT2)

Gründemann¹,

Hahne²,

Berkels³

et al. 2003

The Journal of Pharmacology and Experimental Therapeutics

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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 nonexocytotic 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 [3 H]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.In recent years, agmatine has been recognized as an extracellular signaling substance in mammalia. Agmatine [1-(4-aminobutyl)guanidine] is an amine, synthesized by decarboxylation of L-arginine by arginine decarboxylase. Arginine decarboxylase activity is associated with mitochondrial membranes and is most prevalent in kidney, liver, and brain (Lortie et al., 1996). Agmatine is present in plasma and is widely but unevenly distributed in mammalian tissue (Raasch et al., 1995).There is evidence that agmatine acts as an antiproliferative molecule through induction of the protein antizyme (Satriano et al., 1998;Babal et al., 2001). Antizyme inhibits ornithine decarboxylase and hence polyamine (putrescine, spermine, and spermidine) biosynthesis. At the same time, antizyme suppresses polyamine uptake. Concerted intracellular polyamine depletion eventually leads to growth arrest. Thus, agmatine has been considered a tumor suppressor in the control of cellular proliferation (Satriano et al., 1999). In addition, agmatine might serve as a neurotransmitter or neuromodulator. It is synthesized in specific regions of the brain, stored in synaptic vesicles, released by depolarization, and inactivated by agmatinase and diamine oxidase (Li et al., 1994). Moreover, agmatine binds to ␣ 2 -adrenoceptors and imidazoline binding sites, and blocks NMDA receptor channels and other ligand-gated cation channels. It also inhibits nitric oxide synthase and induces release of peptide hormones. Although the precise function of endogenously released agmatine in the central nervous system is presently still unclear, ...

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Expression of the extraneuronal monoamine transporter (uptake2) in human glioma cells

Cited by 45 publications

References 36 publications

Organic Cation Transporter 3 (Slc22a3) Is Implicated in Salt-Intake Regulation

Organic Cation Transporter 3 (Slc22a3) Is Implicated in Salt-Intake Regulation

Identity of the Organic Cation Transporter OCT3 as the Extraneuronal Monoamine Transporter (uptake2) and Evidence for the Expression of the Transporter in the Brain

Agmatine Is Efficiently Transported by Non-Neuronal Monoamine Transporters Extraneuronal Monoamine Transporter (EMT) and Organic Cation Transporter 2 (OCT2)

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