Cited by 374Neuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on BehaviorReceptor Mechanisms and Signaling

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Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter

Gründemann, Dirk, Schechinger, Birgit, Rappold, Gudrun, Schömig, Edgar·1998·Nature Neuroscience

DOI 10.1038/1557

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“3 kDa for deglycosylated EMT (Gründemann et al. 1998), which is very similar in size to the glial EMT protein described here (63 kDa).”
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“(who identified it as the extraneuronal monoamine transporter) in Caki-1 cells (a human kidney carcinoma cell line) [17], by Kekuda et al.”
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“However, OCT3 does not recognize choline as a substrate [6–10].”
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“Oct3 was independently cloned from rat brain and placenta [35,36], while human OCT3 was cloned from Caki-1 cells and originally identified as an extraneuronal monoamine transporter [37].”
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“…and consistent with a contribution to HPA axis-related impairment of 5-HT clearance, OCT3 is widely expressed in forebrain targets of glucocorticoids, including hippocampus (Gasser et al., 2009), and is functionally inhibited by corticosterone (Gründemann et al., 1998; Gasser et al., 2006).”
Background
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“It also clears monoamines, including catecholamines and 5-HT, from the extracellular space [21], and hence its blockade is expected to increase the extracellular concentrations of these agents.”
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“Cortisol blocks extraneuronal catecholamine transporters, and thus expands the effects of catecholamines [80].”
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“Finally, SLC22A3 encodes the organic cation transporter 3 (OCT3) which has been implicated in the transport and subsequent regulation of concentrations of METH as well as dopamine and serotonin in the brain [Grundemann et al., 1998; Wu et al., 1998].”
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“Human OCT3 consists of 556 residues and shows a broad distribution with strong expression in liver, placenta, heart, and skeletal muscle.(86,87) In terms of subcellular localization, OCT1/3 have been localized to the sinusoidal (basolateral) membrane of hepatocytes in rat and human liver, OCT1-3 to the basolateral mem…”
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Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule.
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“Type II includes a variety of cations, such as tetrapentylammonium [50, 79], decynium 22 [76], and disprocynium24 [80].”
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“Additional file 1: Summary of rapid effects of corticosteroids and estrogens on the central nervous system [148-181].”
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Local inhibition of organic cation transporters increases extracellular serotonin in the medial hypothalamus.
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“2004), and with its previously described role as a transporter mediating the uptake of extracellular monoamines (Grundemann et al. 1998).”
BackgroundInfluential
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“tissues including heart [(30, 43), reviewed in (54)], which”
The localisation of the extraneuronal monoamine transporter (EMT) in rat brain
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“Functionally, it was long known as (uptake2) (Iversen and Salt 1965) and identified on a molecular basis in 1998 (Gründemann et al. 1998; Kekuda et al. 1998).”
BackgroundMethodInfluentialSelf-citation
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Lazar, A., Walitza, S., Jetter, A., Gerlach, M., Warnke, A., Herpertz-Dahlmann, B., Gründemann, D., Grimberg, G., Schulz, E., Remschmidt, H., et al. (2008) · International Journal of Neuropsychopharmacology · doi:10.1017/s1461145707007742 · Cited by 51
“…monoamine transporter (EMT) has been identified as the molecular correlate of the classical uptake system responsible for the non-neuronal inactivation of circulating and centrally released catecholamines, especially of norepinephrine and to a lesser extent of 5-HT (Gründemann et al., 1998).”
BackgroundInfluentialSelf-citation
Association between gene polymorphisms of SLC22A3 and methamphetamine use disorder.
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“We showed that: (1) NE uptake was time-dependent, with a time course expected for an uptake mechanism as shown by others (11, 12, 20, 31); (2) NE uptake rate was concentration-dependent, with an estimated Km value in the range of those previously published (25, 32, 33); and (3) a near-linear correlation exists between…”
BackgroundResult
Serotonin in the Ventral Hippocampus Modulates Anxiety-Like Behavior during Amphetamine Withdrawal
Tu, W., Cook, A., Scholl, J., Mears, M., Watt, M., Renner, K., & Forster, G. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.09.019 · Cited by 48
“For instance, the OCT 3 is a polyspecific low-affinity but high-capacity transporter that functions in the clearance of cations including 5-HT (Grundemann et al., 1998; Koepsell et al., 2007; Daws, 2009), and is believed to contribute to the regulation of extracellular 5-HT especially when concentrations are elevated…”
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“The uptake2 transporters, such as the extraneuronal monoamine transporters (EMT), display distinct pharmacological profiles compared to the monoamine uptake1 transporters and were identified several years after the monoamine uptake1 [50, 51].”
Background
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Multiple binding sites in organic cation transporters require sophisticated procedures to identify interactions of novel drugs
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“Other than these high-affinity amine transporters, additional transporters for biogenic amines in the brain have been identified, such as OCT (Gründemann et al., 1998; Eisenhofer, 2001; Vialou et al., 2004; Amphoux et al., 2006; Koepsell et al., 2007) and PMAT (Engel et al., 2004; Engel and Wang,…”
Background
Comparison between uptake2 and rOCT1: effects of catecholamines, metanephrines and corticosterone
Martel, F., Ribeiro, L., Calhau, C., & Azevedo, I. (1999) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/pl00005356 · Cited by 45
“…was recently shown that rOCT1 accepts the biogenic amines noradrenaline and dopamine as substrates (Busch et al. 1996; Breidert et al. 1997, 1998; Gründemann et al. 1998b), being most probably responsible for the transport of catecholamines from blood into cells in the kidney (Ullrich et al.…”
BackgroundMethodResultInfluential
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“Recently, the transporter OCT3 has been identified to be the mediator of the nonneural uptake-2 mechanism (29,30).”
Background
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Genetic variability of the extraneuronal monoamine transporter EMT (SLC22A3)
Lazar, A., Gründemann, D., Berkels, R., Taubert, D., Zimmermann, T., & Schömig, E. (2003) · Journal of Human Genetics · doi:10.1007/s10038-003-0015-5 · Cited by 32
“Because of its functional profile and expression in sympathetically innervated tissues, EMT is a candidate gene for common disorders such as hypertension, obesity or neuropsychiatric diseases (Gründemann et al. 1998; Eisenhofer 2001).”
BackgroundSelf-citation
Interaction of organic cation transporter 3 (SLC22A3) and amphetamine
Zhu, H.-J., Appel, D. I., Gründemann, D., & Markowitz, J. S. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06738.x · Cited by 39
“The rank order of OCT3 transport efficiency towards these three neurotransmitters was determined to be NE > DA > 5-HT based on the ratios of Vmax to Km, which is likewise in agreement with other published investigations (Grundemann et al. 1998; Amphoux et al. 2006).”
BackgroundMethodResultInfluentialSelf-citation
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Emotion-induced retrograde amnesia varies as a function of noradrenergic-glucocorticoid activity
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Natural and synthetic corticosteroids inhibit uptake2-mediated transport in CNS neurons
Hill, J. E., Makky, K., Shrestha, L., Hillard, C. J., & Gasser, P. J. (2010) · Physiology & Behavior · doi:10.1016/j.physbeh.2010.11.012 · Cited by 37
“As shown in Figure 1, mRNAs for OCT1, OCT3, and PMAT were clearly detected in CGNs, while mRNA for SERT was detected at very low levels, and mRNAs for OCT2, DAT, and NET were not detected.”
Influential
Functional characterization of Na+-independent choline transport in primary cultures of neurons from mouse cerebral cortex.
Fujita, T., Shimada, A., Okada, N., & Yamamoto, A. (2006) · Neuroscience Letters · doi:10.1016/j.neulet.2005.09.069 · Cited by 36
Interaction of the human plasma membrane monoamine transporter (hPMAT) with antidepressants and antipsychotics
Haenisch, B., & Bönisch, H. (2009) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-009-0479-8 · Cited by 36
Roles for the uptake2 transporter OCT3 in regulation of dopaminergic neurotransmission and behavior
Gasser, P. (2018) · Neurochemistry International · doi:10.1016/j.neuint.2018.07.008 · Cited by 35
Organic cation transporter 3: A cellular mechanism underlying rapid, non-genomic glucocorticoid regulation of monoaminergic neurotransmission, physiology, and behavior
Gasser, P. J., & Lowry, C. A. (2018) · Hormones and Behavior · doi:10.1016/j.yhbeh.2018.05.003 · Cited by 40
Uptake of mIBG and catecholamines in noradrenaline- and organic cation transporter-expressing cells: potential use of corticosterone for a preferred uptake in neuroblastoma- and pheochromocytoma cells.
Bayer, M., Kuçi, Z., Schömig, E., Gründemann, D., Dittmann, H., Handgretinger, R., & Bruchelt, G. (2009) · Nuclear Medicine and Biology · doi:10.1016/j.nucmedbio.2008.12.010 · Cited by 34
Self-citation
CB1 receptor mediates the effects of glucocorticoids on AMPK activity in the hypothalamus
Scerif, M., Füzesi, T., Thomas, J., Kola, B., Grossman, A. B., Fekete, C., & Korbonits, M. (2013) · Journal of Endocrinology · doi:10.1530/joe-13-0192 · Cited by 36
“One possible explanation for the CB1-independent stimulatory effect of glucocorticoids on cardiac AMPK is the inhibitory effect of glucocorticoids on noradrenaline reuptake in the heart (Grundemann et al. 1998).”
Background
Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia
Arnsten, A. F. T., Woo, E., Yang, S., Wang, M., & Datta, D. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.02.003 · Cited by 35
“Glucocorticoids are known to block the extraneuronal catecholamine transporters on glia that normally serve to remove catecholamines from the extracellular space (60), which would exacerbate the stress response.”
General Overview of Organic Cation Transporters in Brain
Koepsell, H. (2021) · Handbook of experimental pharmacology · doi:10.1007/164_2021_449 · Cited by 42
Human Organic Cation Transporters 1 (SLC22A1), 2 (SLC22A2), and 3 (SLC22A3) as Disposition Pathways for Fluoroquinolone Antimicrobials
Mulgaonkar, A., Venitz, J., Gründemann, D., & Sweet, D. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02289-12 · Cited by 32
“Previous work found hOCT1-mediated TEA accumulation in HEK293 cells to be linear with time through at least 2 min and reported a Michaelis-Menten constant (Km) value of 229 M for TEA (10, 25), and we obtained similar results in our laboratory (Km 296 34 M).”
MethodResultSelf-citation
Functional map of TEA transport activity in isolated rabbit renal proximal tubules.
Wright, S., Evans, K., Zhang, X., Cherrington, N., Sitar, D., & Dantzler, W. (2004) · AJP - Renal Physiology · doi:10.1152/ajprenal.00115.2004 · Cited by 32
OCTs, OATs, and OCTNs: structure and function of the polyspecific organic ion transporters of the SLC22 family
Volk, C. (2014) · Wiley Interdisciplinary Reviews Membrane Transport and Signalling · doi:10.1002/wmts.100 · Cited by 32
Neurotoxic catecholamine metabolite in nociceptors contributes to painful peripheral neuropathy
Dina, O. A., Khasar, S. G., Alessandri‐Haber, N., Bogen, O., Chen, X., Green, P. G., Reichling, D. B., Messing, R. O., & Levine, J. D. (2008) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2008.06425.x · Cited by 32
“Of note in this regard, NET expression is regulated by a variety of signals (Paczkowski et al., 1996; Jahng et al., 1998; Zahniser & Doolen, 2001; Hara et al., 2002; Mao et al., 2005; Habecker et al., 2006), including glucocorticoids (Grundemann et al., 1998; Eisenhofer, 2001).”
Background
The role of organic cation transporter-3 in methamphetamine disposition and its behavioral response in rats
Nakayama, H., Kitaichi, K., Ito, Y., Hashimoto, K., Takagi, K., Yokoi, T., Takagi, K., Ozaki, N., Yamamoto, T., & Hasegawa, T. (2007) · Brain Research · doi:10.1016/j.brainres.2007.09.072 · Cited by 28
“OCT3 is expressed in several tissues including the placenta, intestine, heart and brain, and transporter (Grundemann et al., 1997, 1998; Kekuda et al., 1998).”
Background
A decrease in the plasma DHEA to cortisol ratio during smoking abstinence may predict relapse: a preliminary study
Rasmusson, A. M., Wu, R., Paliwal, P., Anderson, G. M., & Krishnan‐Sarin, S. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0367-6 · Cited by 33
“Both cross the blood– brain barrier (Compagnone and Mellon 2000) and exert, by direct action or the activity of metabolites (Rose et al. 1997; Grundemann et al. 1998; Morfin and Starka 2001), important metabolic, neuromodulatory, neurogenetic, and epigenetic effects in the brain (Kimonides et al.…”
Background
Osmotic swelling-provoked release of organic osmolytes in human intestinal epithelial cells
Tomassen, S. F. B., Fekkes, D., de Jonge, H. R., & Tilly, B. C. (2004) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00468.2003 · Cited by 29
Substrates and Inhibitors of the Organic Cation Transporter 3 and Comparison with OCT1 and OCT2.
Gebauer, L., Jensen, O., Brockmöller, J., & Dücker, C. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c01075 · Cited by 30
Interaction of Ethambutol with Human Organic Cation Transporters of the SLC22 Family Indicates Potential for Drug-Drug Interactions during Antituberculosis Therapy
Pan, X., Wang, L., Gründemann, D., & Sweet, D. (2013) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01255-13 · Cited by 30
Self-citation
Blockade of the high‐affinity noradrenaline transporter (NET) by the selective 5‐HT reuptake inhibitor escitalopram: anin vivomicrodialysis study in mice
Nguyen, H. T., Guiard, B. P., Bacq, A., David, D. J. P., Mendez‐David, I., Quesseveur, G., Gautron, S., Sánchez, C., & Gardier, A. M. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.01850.x · Cited by 38
Functional analysis of [methyl-(3)H]choline uptake in glioblastoma cells: Influence of anti-cancer and central nervous system drugs.
Taguchi, C., Inazu, M., Saiki, I., Yara, M., Hara, N., Yamanaka, T., & Uchino, H. (2014) · Biochemical Pharmacology · doi:10.1016/j.bcp.2014.01.033 · Cited by 29
Organic cation transporter 3 is densely expressed in the intercalated cell groups of the amygdala: Anatomical evidence for a stress hormone-sensitive dopamine clearance system
Hill, J. E., & Gasser, P. J. (2013) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2013.04.007 · Cited by 27
“Interestingly, OCT3-mediated transport is directly and acutely inhibited by the stress hormone corticosterone (Grundemann et al., 1998).”
Influential
Role of Neuronal KATP Channels and Extraneuronal Monoamine Transporter on Norepinephrine Overflow in a Model of Myocardial Low Flow Ischemia
Burgdorf, C., Dendorfer, A., Kurz, T., Schömig, E., Stölting, I., Schütte, F., & Richardt, G. (2004) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.103.059832 · Cited by 28
“Recently, molecular identification of the extraneuronal monoamine transporter (EMT, uptake2) has been reported (Gründemann et al., 1998; Gründemann and Schömig, 2000).”
BackgroundSelf-citation
Activation of the extraneuronal monoamine transporter (EMT) from rat expressed in 293 cells
Gründemann, D., Koschker, A., Haag, C., Honold, C., Zimmermann, T., & Schömig, E. (2002) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704926 · Cited by 28
Self-citation
Uptake of Pramipexole by Human Organic Cation Transporters
Diao, L., Shu, Y., & Polli, J. E. (2010) · Molecular Pharmaceutics · doi:10.1021/mp100036b · Cited by 28
Expression and functional characterization of choline transporter in human keratinocytes.
Uchida, Y., Inazu, M., Takeda, H., Yamada, T., Tajima, H., & Matsumiya, T. (2009) · Journal of Pharmacological Sciences · doi:10.1254/jphs.08291fp · Cited by 27
Modulation of MPP+ uptake by procyanidins in Caco‐2 cells: Involvement of oxidation/reduction reactions
Faria, A., Mateus, N., de Freitas, V., & Calhau, C. (2006) · FEBS Letters · doi:10.1016/j.febslet.2005.11.068 · Cited by 27
“domain and four in intracellular domains [26].”
Antidepressant efficacy of a selective organic cation transporter blocker in a mouse model of depression
Orrico‐Sánchez, A., Chausset‐Boissarie, L., de Sousa, R. A., Coutens, B., Amin, S. R., Vialou, V., Louis, F., Hessani, A., Dansette, P. M., Zornoza, T., et al. (2019) · Molecular Psychiatry · doi:10.1038/s41380-019-0548-4 · Cited by 33
“D24 is a potent and relatively selective OCT inhibitor, interacting with a putative high-affinity binding site of these transporters [16] and affinity constants ranging from 15 to 280 nM for brain OCT [17, 18].”
Background
Corticosterone Potentiation of Cocaine-Induced Reinstatement of Conditioned Place Preference in Mice is Mediated by Blockade of the Organic Cation Transporter 3
McReynolds, J. R., Taylor, A., Vranjkovic, O., Ambrosius, T., Derricks, O., Nino, B., Kurtoglu, B., Wheeler, R. A., Baker, D. L., Gasser, P. J., et al. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2016.187 · Cited by 29
Organic cation transporter 3 and the dopamine transporter differentially regulate catecholamine uptake in the basolateral amygdala and nucleus accumbens
Holleran, K. M., Rose, J. H., Fordahl, S., Benton, K. C., Rohr, K. E., Gasser, P., & Jones, S. R. (2020) · European Journal of Neuroscience · doi:10.1111/ejn.14927 · Cited by 25
Identification of genes directly responding to DLK1 signaling in Callipyge sheep
Yu, H. M., Waddell, J. N., Kuang, S., Tellam, R. L., Cockett, N., & Bidwell, C. A. (2018) · BMC Genomics · doi:10.1186/s12864-018-4682-1 · Cited by 24

Authors: Gründemann, D., Schechinger, B., Rappold, G., & Schömig, E.
Affiliations: Heidelberg University (DE)
Corresponding author: Gründemann, Dirk
ORCID: Gründemann, Dirk
Rappold, Gudrun
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 1998-09
Volume: 1
Issue: 5
Pages: 349-351
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/1557
OpenAlex: W1493374490
Cited by: 374
References: 0
Citations by year: 2026: 2 · 2025: 2 · 2024: 4 · 2023: 10 · 2022: 13 · 2021: 13 · 2020: 9 · 2019: 11 · 2018: 9 · 2017: 8 · 2016: 16 · 2015: 13 · 2014: 17 · 2013: 25 · 2012: 13
FWCI: 5.15
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
Keywords: sympathetic innervation, pharmacological characterization
MeSH terms: Organic Cation Transporter 3, Amino Acid Sequence, Animals, Carrier Proteins, Cell Line, Chromosome Mapping, Chromosomes, Human, Pair 6, Corticosterone, Humans, Kinetics, Molecular Sequence Data, Myocardium, Norepinephrine, 1-Methyl-4-phenylpyridinium, Organic Cation Transport Proteins, Rats

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Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter

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