Abstract
Catecholamines, including dopamine, norepinephrine, and epinephrine, are modulatory transmitters released from specialized neurons throughout the brain. Collectively, catecholamines exert powerful regulation of mood, motivation, arousal, and plasticity. Transporter-mediated uptake determines the peak concentration, duration, and physical spread of released catecholamines, thus playing key roles in determining the magnitude and duration of their modulatory effects. Most studies of catecholamine clearance have focused on the presynaptic high-affinity, low-capacity dopamine (DAT), and norepinephrine (NET) transporters, which are members of the uptake1 family of monoamine transporters. However, recent studies have demonstrated that members of the uptake2 family of monoamine transporters, including organic cation transporter 2 (OCT2), OCT3, and the plasma membrane monoamine transporter (PMAT) are expressed widely throughout the brain. In contrast to DAT and NET, these transporters have higher capacity and lower affinity for catecholamines and are multi-specific, each with the capacity to transport all catecholamines. The expression of these transporters in the brain suggests that they play significant roles in regulating catecholamine homeostasis. This review summarizes studies describing the anatomical distribution of OCT2, OCT3, and PMAT, their cellular and subcellular localization, and their contribution to the regulation of the clearance of catecholamines in the brain.
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References
Amphoux A, Vialou V, Drescher E et al (2006) Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology 50:941–952. https://doi.org/10.1016/j.neuropharm.2006.01.005
Bacq A, Balasse L, Biala G et al (2012) Organic cation transporter 2 controls brain norepinephrine and serotonin clearance and antidepressant response. Mol Psychiatry 17:926–939. https://doi.org/10.1038/mp.2011.87
Baganz NL, Horton RE, Calderon AS et al (2008) Organic cation transporter 3: keeping the brake on extracellular serotonin in serotonin-transporter-deficient mice. Proc Natl Acad Sci U S A 105:18976–18981. https://doi.org/10.1073/pnas.0800466105
Boivin B, Lavoie C, Vaniotis G et al (2006) Functional β-adrenergic receptor signalling on nuclear membranes in adult rat and mouse ventricular cardiomyocytes. Cardiovasc Res 71:69–78. https://doi.org/10.1016/j.cardiores.2006.03.015
Bowman MA, Mitchell NC, Owens WA et al (2020) Effect of concurrent organic cation transporter blockade on norepinephrine clearance inhibiting- and antidepressant-like actions of desipramine and venlafaxine. Eur J Pharmacol 883:173285. https://doi.org/10.1016/j.ejphar.2020.173285
Breidert T, Spitzenberger F, Gründemann D, Schömig E (1998) Catecholamine transport by the organic cation transporter type 1 (OCT1). Br J Pharmacol 125:218–224. https://doi.org/10.1038/sj.bjp.0702065
Couroussé T, Bacq A, Belzung C et al (2015) Brain organic cation transporter 2 controls response and vulnerability to stress and GSK3β signaling. Mol Psychiatry 20:889–900. https://doi.org/10.1038/mp.2014.86
Cui M, Aras R, Christian WV et al (2009) The organic cation transporter-3 is a pivotal modulator of neurodegeneration in the nigrostriatal dopaminergic pathway. Proc Natl Acad Sci 106:8043–8048. https://doi.org/10.1073/pnas.0900358106
Dahlin A, Xia L, Kong W et al (2007) Expression and immunolocalization of the plasma membrane monoamine transporter in the brain. Neuroscience 146:1193–1211. https://doi.org/10.1016/j.neuroscience.2007.01.072
Droste SK, de Groote L, Atkinson HC et al (2008) Corticosterone levels in the brain show a distinct Ultradian rhythm but a delayed response to forced swim stress. Endocrinology 149:3244–3253. https://doi.org/10.1210/en.2008-0103
Droste SK, Groote LD, Lightman SL et al (2009) The Ultradian and circadian rhythms of free corticosterone in the brain are not affected by gender: an in vivo microdialysis study in Wistar rats. J Neuroendocrinol 21:132–140. https://doi.org/10.1111/j.1365-2826.2008.01811.x
Duan H, Wang J (2010) Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther 335:743–753. https://doi.org/10.1124/jpet.110.170142
Duan H, Wang J (2013) Impaired monoamine and organic cation uptake in choroid plexus in mice with targeted disruption of the plasma membrane monoamine transporter (Slc29a4) gene*. J Biol Chem 288:3535–3544. https://doi.org/10.1074/jbc.m112.436972
Engel K, Wang J (2005) Interaction of organic cations with a newly identified plasma membrane monoamine transporter. Mol Pharmacol 68:1397–1407. https://doi.org/10.1124/mol.105.016832
Gasser PJ, Lowry CA, Orchinik M (2006) Corticosterone-sensitive monoamine transport in the rat dorsomedial hypothalamus: potential role for organic cation transporter 3 in stress-induced modulation of monoaminergic neurotransmission. J Neurosci 26:8758–8766. https://doi.org/10.1523/jneurosci.0570-06.2006
Gasser PJ, Orchinik M, Raju I, Lowry CA (2009) Distribution of organic cation transporter 3, a corticosterone-sensitive monoamine transporter, in the rat brain. J Comp Neurol 512:529–555. https://doi.org/10.1002/cne.21921
Gasser PJ, Lowry CA (2018) Organic cation transporter 3: a cellular mechanism underlying rapid, nongenomic glucocorticoid regulation of monoaminergic neurotransmission, physiology, and behavior. Horm Beh 104:173–182
Gasser PJ, Hurley MM, Chan J, Pickel VM (2016) Organic cation transporter 3 (OCT3) is localized to intracellular and surface membranes in select glial and neuronal cells within the basolateral amygdaloid complex of both rats and mice. Brain Struct Funct 222:1913–1928. https://doi.org/10.1007/s00429-016-1315-9
Graf EN, Wheeler RA, Baker DA et al (2013) Corticosterone acts in the nucleus Accumbens to enhance dopamine signaling and potentiate reinstatement of cocaine seeking. J Neurosci 33:11800–11810. https://doi.org/10.1523/jneurosci.1969-13.2013
Gründemann D, Köster S, Kiefer N et al (1998a) Transport of monoamine transmitters by the organic cation transporter type 2, OCT2. J Biol Chem 273:30915–30920. https://doi.org/10.1074/jbc.273.47.30915
Gründemann D, Schechinger B, Rappold GA, Schömig E (1998b) Molecular identification of the corticosterone-sensitive extraneuronal catecholamine transporter. Nat Neurosci 1:349–351. https://doi.org/10.1038/1557
He Q, Wang Q, Yuan C, Wang Y (2017) Downregulation of miR-7116-5p in microglia by MPP+ sensitizes TNF-α production to induce dopaminergic neuron damage. Glia 65:1251–1263. https://doi.org/10.1002/glia.23153
Hill JE, Gasser PJ (2013) 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. J Chem Neuroanat 52:36–43
Hill JE, Makky K, Shrestha L et al (2011) Natural and synthetic corticosteroids inhibit uptake2-mediated transport in CNS neurons. Physiol Behav 104:306–311. https://doi.org/10.1016/j.physbeh.2010.11.012
Holleran KM, Rose JH, Fordahl SC et al (2020) Organic cation transporter 3 and the dopamine transporter differentially regulate catecholamine uptake in the basolateral amygdala and nucleus accumbens. Eur J Neurosci. https://doi.org/10.1111/ejn.14927
Horton RE, Apple DM, Owens AW et al (2013) Decynium-22 enhances SSRI-induced antidepressant-like effects in mice: uncovering novel targets to treat depression. J Neurosci 33:10534–10543. https://doi.org/10.1523/jneurosci.5687-11.2013
Inazu M, Takeda H, Matsumiya T (2002) Expression and functional characterization of the extraneuronal monoamine transporter in normal human astrocytes. J Neurochem 84:43–52. https://doi.org/10.1046/j.1471-4159.2003.01566.x
Inazu M, Takeda H, Matsumiya T (2003) Functional expression of the norepinephrine transporter in cultured rat astrocytes. J Neurochem 84:136–144
Irannejad R, Pessino V, Mika D et al (2017) Functional selectivity of GPCR-directed drug action through location bias. Nat Chem Biol 13:nchembio.2389. https://doi.org/10.1038/nchembio.2389
Iversen LL (1965) The uptake of catechol amines at high perfusion concentrations in the rat isolated heart: a novel catechol uptake process. Br J Pharm Chemother 25:18–33. https://doi.org/10.1111/j.1476-5381.1965.tb01753.x
Iversen LL, Salt PJ (1970) Inhibition of catecholamine Uptake-2 by steroids in the isolated rat heart. Br J Pharmacol 40:528–530. https://doi.org/10.1111/j.1476-5381.1970.tb10637.x
Li L, He M, Zhou L et al (2015) A solute carrier family 22 member 3 variant rs3088442 G→A associated with coronary heart disease inhibits lipopolysaccharide-induced inflammatory response. J Biol Chem 290:5328–5340. https://doi.org/10.1074/jbc.m114.584953
Lloyd JT, Martini A, McDouall A et al (2019) Electrophysiological characterization of novel effects of the Uptake-2 blocker Decynium-22 (D-22) on dopaminergic neurons in the substantia Nigra pars compacta. Neuroscience 396:154–165. https://doi.org/10.1016/j.neuroscience.2018.11.005
Mayer FP, Schmid D, Owens WA et al (2018) An unsuspected role for organic cation transporter 3 in the actions of amphetamine. Neuropsychopharmacology 43:2408–2417. https://doi.org/10.1038/s41386-018-0053-5
Nakata T, Matsui T, Kobayashi K et al (2013) Organic cation transporter 2 (SLC22A2), a low-affinity and high-capacity choline transporter, is preferentially enriched on synaptic vesicles in cholinergic neurons. Neuroscience 252:212–221. https://doi.org/10.1016/j.neuroscience.2013.08.011
Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine-and antidepressant-sensitive human noradrenaline transporter. Nature 350:350–354. https://doi.org/10.1038/350350a0
Perdan-Pirkmajer K, Pirkmajer S, Černe K, Kržan M (2012) Molecular and kinetic characterization of histamine transport into adult rat cultured astrocytes. Neurochem Int 61:415–422. https://doi.org/10.1016/j.neuint.2012.05.002
Qian X, Droste SK, Lightman SL et al (2012) Circadian and Ultradian rhythms of free glucocorticoid hormone are highly synchronized between the blood, the subcutaneous tissue, and the brain. Endocrinology 153:4346–4353. https://doi.org/10.1210/en.2012-1484
Russ H, Friedgen B, Königs B et al (1996) Pharmacokinetic and α1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport. Naunyn-Schmiedebergs Arch Pharmacol 354:268–274. https://doi.org/10.1007/bf00171057
Sader-Mazbar O, Loboda Y, Rabey MJ, Finberg JPM (2013) Increased L-DOPA-derived dopamine following selective MAO-A or -B inhibition in rat striatum depleted of dopaminergic and serotonergic innervation. Br J Pharmacol 170:999–1013. https://doi.org/10.1111/bph.12349
Schömig E, Lazar A, Gründemann D (2006) Neurotransmitter transporters. Handb Exp Pharmacol:151–180. https://doi.org/10.1007/3-540-29784-7_8
Shang T, Uihlein AV, Asten J et al (2003) 1-Methyl-4-phenylpyridinium accumulates in cerebellar granule neurons via organic cation transporter 3. J Neurochem 85:358–367. https://doi.org/10.1046/j.1471-4159.2003.01686.x
Takeda H, Inazu M, Matsumiya T (2002) Astroglial dopamine transport is mediated by norepinephrine transporter. Naunyn Schmiedebergs Arch Pharmacol 366:620–623. https://doi.org/10.1007/s00210-002-0640-0
Vialou V, Amphoux A, Zwart R et al (2004) Organic cation transporter 3 (Slc22a3) is implicated in Salt-intake regulation. J Neurosci 24:2846–2851. https://doi.org/10.1523/jneurosci.5147-03.2004
Vialou V, Balasse L, Dumas S et al (2007) Neurochemical characterization of pathways expressing plasma membrane monoamine transporter in the rat brain. Neuroscience 144:616–622. https://doi.org/10.1016/j.neuroscience.2006.09.058
Vialou V, Balasse L, Callebert J et al (2008) Altered aminergic neurotransmission in the brain of organic cation transporter 3-deficient mice. J Neurochem 106:1471–1482. https://doi.org/10.1111/j.1471-4159.2008.05506.x
Wang J (2016) The plasma membrane monoamine transporter (PMAT): structure, function, and role in organic cation disposition. Clin Pharmacol Ther 100:489–499. https://doi.org/10.1002/cpt.442
Wheeler DS, Ebben AL, Kurtoglu B, Lovell ME, Bohn AT, Jasek IA, Baker DA, Mantsch JR, Gasser PJ, Wheeler RA (2017) Corticosterone regulates both naturally occurring and cocaine-induced dopamine signaling by selectively decreasing dopamine uptake. Eur J Neurosci 46(10):2638–2646
Wu X, Kekuda R, Huang W et al (1998) Identity of the organic cation transporter OCT3 as the Extraneuronal monoamine transporter (uptake2) and evidence for the expression of the transporter in the brain. J Biol Chem 273:32776–32786. https://doi.org/10.1074/jbc.273.49.32776
Wu SC, Dahl EF, Wright CD et al (2014) Nuclear localization of a1A-adrenergic receptors is required for signaling in cardiac myocytes: an “inside-out” a1-AR signaling pathway. J Am Heart Assoc 3:e000145
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Gasser, P.J. (2021). Organic Cation Transporters in Brain Catecholamine Homeostasis. In: Daws, L.C. (eds) Organic Cation Transporters in the Central Nervous System. Handbook of Experimental Pharmacology, vol 266. Springer, Cham. https://doi.org/10.1007/164_2021_470
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DOI: https://doi.org/10.1007/164_2021_470
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