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SLC10A4 Is a Vesicular Amine-Associated Transporter Modulating Dopamine Homeostasis

      Abstract

      Background

      The neuromodulatory transmitters, biogenic amines, have profound effects on multiple neurons and are essential for normal behavior and mental health. Here we report that the orphan transporter SLC10A4, which in the brain is exclusively expressed in presynaptic vesicles of monoaminergic and cholinergic neurons, has a regulatory role in dopamine homeostasis.

      Methods

      We used a combination of molecular and behavioral analyses, pharmacology, and in vivo amperometry to assess the role of SLC10A4 in dopamine-regulated behaviors.

      Results

      We show that SLC10A4 is localized on the same synaptic vesicles as either vesicular acetylcholine transporter or vesicular monoamine transporter 2. We did not find evidence for direct transport of dopamine by SLC10A4; however, synaptic vesicle preparations lacking SLC10A4 showed decreased dopamine vesicular uptake efficiency. Furthermore, we observed an increased acidification in synaptic vesicles isolated from mice overexpressing SLC10A4. Loss of SLC10A4 in mice resulted in reduced striatal serotonin, noradrenaline, and dopamine concentrations and a significantly higher dopamine turnover ratio. Absence of SLC10A4 led to slower dopamine clearance rates in vivo, which resulted in accumulation of extracellular dopamine. Finally, whereas SLC10A4 null mutant mice were slightly hypoactive, they displayed hypersensitivity to administration of amphetamine and tranylcypromine.

      Conclusions

      Our results demonstrate that SLC10A4 is a vesicular monoaminergic and cholinergic associated transporter that is important for dopamine homeostasis and neuromodulation in vivo. The discovery of SLC10A4 and its role in dopaminergic signaling reveals a novel mechanism for neuromodulation and represents an unexplored target for the treatment of neurological and mental disorders.

      Keywords

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      References

        • Fuxe K.
        • Dahlstrom A.
        • Hoistad M.
        • Marcellino D.
        • Jansson A.
        • Rivera A.
        • et al.
        From the Golgi-Cajal mapping to the transmitter-based characterization of the neuronal networks leading to two modes of brain communication: Wiring and volume transmission.
        Brain Res Rev. 2007; 55: 17-54
        • Lewis P.R.
        • Shute C.C.
        The distribution of cholinesterase in cholinergic neurons demonstrated with the electron microscope.
        J Cell Sci. 1966; 1: 381-390
        • Eriksson K.S.
        • Sergeeva O.A.
        • Haas H.L.
        • Selbach O.
        Orexins/hypocretins and aminergic systems.
        Acta Physiol (Oxf). 2010; 198: 263-275
        • Kollonitsch J.
        • Perkins L.M.
        • Patchett A.A.
        • Doldouras G.A.
        • Marburg S.
        • Duggan D.E.
        • et al.
        Selective inhibitors of biosynthesis of aminergic neurotransmitters.
        Nature. 1978; 274: 906-908
        • Mann J.J.
        • Stanley M.
        • Gershon S.
        • Rossor M.
        Mental symptoms in Huntington’s disease and a possible primary aminergic neuron lesion.
        Science. 1980; 210: 1369-1371
        • Eiden L.E.
        • Schafer M.K.
        • Weihe E.
        • Schutz B.
        The vesicular amine transporter family (SLC18): Amine/proton antiporters required for vesicular accumulation and regulated exocytotic secretion of monoamines and acetylcholine.
        Pflugers Arch. 2004; 447: 636-640
        • Alfonso A.
        • Grundahl K.
        • Duerr J.S.
        • Han H.P.
        • Rand J.B.
        The Caenorhabditis elegans unc-17 gene: A putative vesicular acetylcholine transporter.
        Science. 1993; 261: 617-619
        • Beaulieu J.M.
        • Gainetdinov R.R.
        The physiology, signaling, and pharmacology of dopamine receptors.
        Pharmacol Rev. 2011; 63: 182-217
        • Castellanos F.X.
        • Tannock R.
        Neuroscience of attention-deficit/hyperactivity disorder: The search for endophenotypes.
        Nat Rev Neurosci. 2002; 3: 617-628
        • Geyer J.
        • Wilke T.
        • Petzinger E.
        The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships.
        Naunyn Schmiedebergs Arch Pharmacol. 2006; 372: 413-431
        • Enjin A.
        • Rabe N.
        • Nakanishi S.T.
        • Vallstedt A.
        • Gezelius H.
        • Memic F.
        • et al.
        Identification of novel spinal cholinergic genetic subtypes disclose Chodl and Pitx2 as markers for fast motor neurons and partition cells.
        J Comp Neurol. 2010; 518: 2284-2304
        • Geyer J.
        • Fernandes C.F.
        • Doring B.
        • Burger S.
        • Godoy J.R.
        • Rafalzik S.
        • et al.
        Cloning and molecular characterization of the orphan carrier protein Slc10a4: Expression in cholinergic neurons of the rat central nervous system.
        Neuroscience. 2008; 152: 990-1005
        • Abe T.
        • Kanemitu Y.
        • Nakasone M.
        • Kawahata I.
        • Yamakuni T.
        • Nakajima A.
        • et al.
        SLC10A4 is a protease-activated transporter that transports bile acids.
        J Biochem. 2013; 154: 93-101
        • Zelano J.
        • Mikulovic S.
        • Patra K.
        • Kuhnemund M.
        • Larhammar M.
        • Emilsson L.
        • et al.
        The synaptic protein encoded by the gene Slc10A4 suppresses epileptiform activity and regulates sensitivity to cholinergic chemoconvulsants.
        Exp Neurol. 2013; 239: 73-81
        • Burger S.
        • Doring B.
        • Hardt M.
        • Beuerlein K.
        • Gerstberger R.
        • Geyer J.
        Co-expression studies of the orphan carrier protein Slc10a4 and the vesicular carriers VAChT and VMAT2 in the rat central and peripheral nervous system.
        Neuroscience. 2011; 193: 109-121
        • Burger S.
        • Döring B.
        • Hardt M.
        • Beuerlein K.
        • Gerstberger R.
        • Geyer J.
        Co-expression studies of the orphan carrier protein SLC10A4 and the vesicular carriers VAChT and VMAT2 in the rat central and peripheral nervous system [published correction appears in Neuroscience 2012;212:226].
        Neuroscience. 2011; 193: 109-121
        • Nirenberg M.J.
        • Liu Y.
        • Peter D.
        • Edwards R.H.
        • Pickel V.M.
        The vesicular monoamine transporter 2 is present in small synaptic vesicles and preferentially localizes to large dense core vesicles in rat solitary tract nuclei.
        Proc Natl Acad Sci U S A. 1995; 92: 8773-8777
        • Ren J.
        • Qin C.
        • Hu F.
        • Tan J.
        • Qiu L.
        • Zhao S.
        • et al.
        Habenula “cholinergic” neurons co-release glutamate and acetylcholine and activate postsynaptic neurons via distinct transmission modes.
        Neuron. 2011; 69: 445-452
        • Jeremic A.
        • Cho W.J.
        • Jena B.P.
        Involvement of water channels in synaptic vesicle swelling.
        Exp Biol Med (Maywood). 2005; 230: 674-680
        • Fredriksson S.
        • Gullberg M.
        • Jarvius J.
        • Olsson C.
        • Pietras K.
        • Gustafsdottir S.M.
        • et al.
        Protein detection using proximity-dependent DNA ligation assays.
        Nat Biotechnol. 2002; 20: 473-477
        • Meyerson B.J.
        • Augustsson H.
        • Berg M.
        • Roman E.
        The Concentric Square Field: A multivariate test arena for analysis of explorative strategies.
        Behav Brain Res. 2006; 168: 100-113
        • Wallen-Mackenzie A.
        • Nordenankar K.
        • Fejgin K.
        • Lagerstrom M.C.
        • Emilsson L.
        • Fredriksson R.
        • et al.
        Restricted cortical and amygdaloid removal of vesicular glutamate transporter 2 in preadolescent mice impacts dopaminergic activity and neuronal circuitry of higher brain function.
        J Neurosci. 2009; 29: 2238-2251
        • Commissiong J.W.
        Monoamine metabolites: Their relationship and lack of relationship to monoaminergic neuronal activity.
        Biochem Pharmacol. 1985; 34: 1127-1131
        • Cransac H.
        • Cottet-Emard J.M.
        • Pequignot J.M.
        • Peyrin L.
        Monoamines (norepinephrine, dopamine, serotonin) in the rat medial vestibular nucleus: Endogenous levels and turnover.
        J Neural Transm. 1996; 103: 391-401
        • Karstaedt P.J.
        • Kerasidis H.
        • Pincus J.H.
        • Meloni R.
        • Graham J.
        • Gale K.
        Unilateral destruction of dopamine pathways increases ipsilateral striatal serotonin turnover in rats.
        Exp Neurol. 1994; 126: 25-30
        • Sharp T.
        • Zetterstrom T.
        • Series H.G.
        • Carlsson A.
        • Grahame-Smith D.G.
        • Ungerstedt U.
        HPLC-EC analysis of catechols and indoles in rat brain dialysates.
        Life Sci. 1987; 41: 869-872
        • Splinter P.L.
        • Lazaridis K.N.
        • Dawson P.A.
        • LaRusso N.F.
        Cloning and expression of SLC10A4, a putative organic anion transport protein.
        World J Gastroenterol. 2006; 12: 6797-6805
        • Wilhelm C.J.
        • Johnson R.A.
        • Lysko P.G.
        • Eshleman A.J.
        • Janowsky A.
        Effects of methamphetamine and lobeline on vesicular monoamine and dopamine transporter-mediated dopamine release in a cotransfected model system.
        J Pharmacol Exp Ther. 2004; 310: 1142-1151
        • Giros B.
        • Jaber M.
        • Jones S.R.
        • Wightman R.M.
        • Caron M.G.
        Hyperlocomotion and indifference to cocaine and amphetamine in mice lacking the dopamine transporter.
        Nature. 1996; 379: 606-612
        • Maycox P.R.
        • Deckwerth T.
        • Hell J.W.
        • Jahn R.
        Glutamate uptake by brain synaptic vesicles. Energy dependence of transport and functional reconstitution in proteoliposomes.
        J Biol Chem. 1988; 263: 15423-15428
        • Sulzer D.
        • Sonders M.S.
        • Poulsen N.W.
        • Galli A.
        Mechanisms of neurotransmitter release by amphetamines: A review.
        Prog Neurobiol. 2005; 75: 406-433
        • Peter D.
        • Jimenez J.
        • Liu Y.
        • Kim J.
        • Edwards R.H.
        The chromaffin granule and synaptic vesicle amine transporters differ in substrate recognition and sensitivity to inhibitors.
        J Biol Chem. 1994; 269: 7231-7237
        • Carlsson A.
        • Hillarp N.A.
        • Waldeck B.
        Analysis of the Mg++-Atp dependent storage mechanism in the amine granules of the adrenal medulla.
        Acta Physiol Scand Suppl. 1963; 215: 1-38
        • Johnson Jr., R.G.
        Accumulation of biological amines into chromaffin granules: A model for hormone and neurotransmitter transport.
        Physiol Rev. 1988; 68: 232-307
        • Desai R.I.
        • Terry P.
        • Katz J.L.
        A comparison of the locomotor stimulant effects of D1-like receptor agonists in mice.
        Pharmacol Biochem Behav. 2005; 81: 843-848
        • Sullivan R.M.
        • Talangbayan H.
        • Einat H.
        • Szechtman H.
        Effects of quinpirole on central dopamine systems in sensitized and non-sensitized rats.
        Neuroscience. 1998; 83: 781-789
        • Villegier A.S.
        • Salomon L.
        • Blanc G.
        • Godeheu G.
        • Glowinski J.
        • Tassin J.P.
        Irreversible blockade of monoamine oxidases reveals the critical role of 5-HT transmission in locomotor response induced by nicotine in mice.
        Eur J Neurosci. 2006; 24: 1359-1365
        • Fon E.A.
        • Pothos E.N.
        • Sun B.C.
        • Killeen N.
        • Sulzer D.
        • Edwards R.H.
        Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action.
        Neuron. 1997; 19: 1271-1283
        • Wang Y.M.
        • Gainetdinov R.R.
        • Fumagalli F.
        • Xu F.
        • Jones S.R.
        • Bock C.B.
        • et al.
        Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine.
        Neuron. 1997; 19: 1285-1296
        • Takahashi N.
        • Miner L.L.
        • Sora I.
        • Ujike H.
        • Revay R.S.
        • Kostic V.
        • et al.
        VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity.
        Proc Natl Acad Sci U S A. 1997; 94: 9938-9943
        • Mooslehner K.A.
        • Chan P.M.
        • Xu W.
        • Liu L.
        • Smadja C.
        • Humby T.
        • et al.
        Mice with very low expression of the vesicular monoamine transporter 2 gene survive into adulthood: Potential mouse model for parkinsonism.
        Mol Cell Biol. 2001; 21: 5321-5331
        • Kim D.S.
        • Szczypka M.S.
        • Palmiter R.D.
        Dopamine-deficient mice are hypersensitive to dopamine receptor agonists.
        J Neurosci. 2000; 20: 4405-4413
        • Brown J.M.
        • Hanson G.R.
        • Fleckenstein A.E.
        Cocaine-induced increases in vesicular dopamine uptake: Role of dopamine receptors.
        J Pharmacol Exp Ther. 2001; 298: 1150-1153
        • Patel J.
        • Mooslehner K.A.
        • Chan P.M.
        • Emson P.C.
        • Stamford J.A.
        Presynaptic control of striatal dopamine neurotransmission in adult vesicular monoamine transporter 2 (VMAT2) mutant mice.
        J Neurochem. 2003; 85: 898-910
        • Carlsson A.
        Drugs acting through dopamine release.
        Pharmacol Ther B. 1975; 1: 401-405
        • Kehr W.
        • Carlsson A.
        • Lindqvist M.
        • Magnusson T.
        • Atack C.
        Evidence for a receptor-mediated feedback control of striatal tyrosine hydroxylase activity.
        J Pharm Pharmacol. 1972; 24: 744-747
        • Kanner B.I.
        • Schuldiner S.
        Mechanism of transport and storage of neurotransmitters.
        CRC Crit Rev Biochem. 1987; 22: 1-38
        • Cooper J.
        • Bloom F.
        • Roth R.
        The Biochemical Basis of Neuropharmacology.
        Oxford University Press, New York2003
        • Jones S.R.
        • Gainetdinov R.R.
        • Jaber M.
        • Giros B.
        • Wightman R.M.
        • Caron M.G.
        Profound neuronal plasticity in response to inactivation of the dopamine transporter.
        Proc Natl Acad Sci U S A. 1998; 95: 4029-4034
        • Chaudhry F.A.
        • Boulland J.L.
        • Jenstad M.
        • Bredahl M.K.
        • Edwards R.H.
        Pharmacology of neurotransmitter transport into secretory vesicles.
        Handb Exp Pharmacol. 2008; : 77-106
        • Stobrawa S.M.
        • Breiderhoff T.
        • Takamori S.
        • Engel D.
        • Schweizer M.
        • Zdebik A.A.
        • et al.
        Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus.
        Neuron. 2001; 29: 185-196
        • Schenck S.
        • Wojcik S.M.
        • Brose N.
        • Takamori S.
        A chloride conductance in VGLUT1 underlies maximal glutamate loading into synaptic vesicles.
        Nat Neurosci. 2009; 12: 156-162
        • Amilhon B.
        • Lepicard E.
        • Renoir T.
        • Mongeau R.
        • Popa D.
        • Poirel O.
        • et al.
        VGLUT3 (vesicular glutamate transporter type 3) contribution to the regulation of serotonergic transmission and anxiety.
        J Neurosci. 2010; 30: 2198-2210
        • Gras C.
        • Amilhon B.
        • Lepicard E.M.
        • Poirel O.
        • Vinatier J.
        • Herbin M.
        • et al.
        The vesicular glutamate transporter VGLUT3 synergizes striatal acetylcholine tone.
        Nat Neurosci. 2008; 11: 292-300
        • Bankston L.A.
        • Guidotti G.
        Characterization of ATP transport into chromaffin granule ghosts. Synergy of ATP and serotonin accumulation in chromaffin granule ghosts.
        J Biol Chem. 1996; 271: 17132-17138
        • Scheel O.
        • Zdebik A.A.
        • Lourdel S.
        • Jentsch T.J.
        Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins.
        Nature. 2005; 436: 424-427
        • Scherman D.
        • Henry J.P.
        Role of the proton electrochemical gradient in monoamine transport by bovine chromaffin granules.
        Biochim Biophys Acta. 1980; 601: 664-677
        • Claro da Silva T.
        • Polli J.E.
        • Swaan P.W.
        The solute carrier family 10 (SLC10): Beyond bile acid transport.
        Mol Aspects Med. 2013; 34: 252-269
        • Laruelle M.
        • Kegeles L.S.
        • Abi-Dargham A.
        Glutamate, dopamine, and schizophrenia: From pathophysiology to treatment.
        Ann N Y Acad Sci. 2003; 1003: 138-158
        • Popova S.N.
        • Alafuzoff I.
        Distribution of SLC10A4, a synaptic vesicle protein in the human brain, and the association of this protein with Alzheimer’s disease-related neuronal degeneration.
        J Alzheimers Dis. 2013; 37: 603-610
        • Borges K.
        Slc10A4—what do we know about the function of this “secret ligand carrier” protein?.
        Exp Neurol. 2013; 248C: 258-261