XB-ART-44225
J Biol Chem
2011 Sep 02;28635:30823-30836. doi: 10.1074/jbc.M111.250308.
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A conserved asparagine residue in transmembrane segment 1 (TM1) of serotonin transporter dictates chloride-coupled neurotransmitter transport.
Henry LK
,
Iwamoto H
,
Field JR
,
Kaufmann K
,
Dawson ES
,
Jacobs MT
,
Adams C
,
Felts B
,
Zdravkovic I
,
Armstrong V
,
Combs S
,
Solis E
,
Rudnick G
,
Noskov SY
,
DeFelice LJ
,
Meiler J
,
Blakely RD
.
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Na(+)- and Cl(-)-dependent uptake of neurotransmitters via transporters of the SLC6 family, including the human serotonin transporter (SLC6A4), is critical for efficient synaptic transmission. Although residues in the human serotonin transporter involved in direct Cl(-) coordination of human serotonin transport have been identified, the role of Cl(-) in the transport mechanism remains unclear. Through a combination of mutagenesis, chemical modification, substrate and charge flux measurements, and molecular modeling studies, we reveal an unexpected role for the highly conserved transmembrane segment 1 residue Asn-101 in coupling Cl(-) binding to concentrative neurotransmitter uptake.
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???displayArticle.pmcLink??? PMC3162443
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R01 DA007259 NIDA NIH HHS , R01 DA008213 NIDA NIH HHS , T32 GM007628 NIGMS NIH HHS , T32 GM008320 NIGMS NIH HHS
Species referenced: Xenopus laevis
Genes referenced: slc6a4 slc6a4l
References [+] :
Abramson,
Structure and function of Na(+)-symporters with inverted repeats.
2009, Pubmed
Abramson, Structure and function of Na(+)-symporters with inverted repeats. 2009, Pubmed
Adams, Ionic currents in the human serotonin transporter reveal inconsistencies in the alternating access hypothesis. 2003, Pubmed , Xenbase
Adams, Flux coupling in the human serotonin transporter. 2002, Pubmed
Adkins, Interactions of tryptamine derivatives with serotonin transporter species variants implicate transmembrane domain I in substrate recognition. 2001, Pubmed
Adragna, Regulation of K-Cl cotransport: from function to genes. 2004, Pubmed
Anisimov, Determination of Electrostatic Parameters for a Polarizable Force Field Based on the Classical Drude Oscillator. 2005, Pubmed
Barker, Transmembrane domain I contributes to the permeation pathway for serotonin and ions in the serotonin transporter. 1999, Pubmed , Xenbase
Barker, High affinity recognition of serotonin transporter antagonists defined by species-scanning mutagenesis. An aromatic residue in transmembrane domain I dictates species-selective recognition of citalopram and mazindol. 1998, Pubmed
Ben-Yona, A glutamine residue conserved in the neurotransmitter:sodium:symporters is essential for the interaction of chloride with the GABA transporter GAT-1. 2011, Pubmed , Xenbase
Beuming, A comprehensive structure-based alignment of prokaryotic and eukaryotic neurotransmitter/Na+ symporters (NSS) aids in the use of the LeuT structure to probe NSS structure and function. 2006, Pubmed
Beuming, The binding sites for cocaine and dopamine in the dopamine transporter overlap. 2008, Pubmed
Binda, Syntaxin 1A interaction with the dopamine transporter promotes amphetamine-induced dopamine efflux. 2008, Pubmed
Blakely, Cloning and expression of a functional serotonin transporter from rat brain. 1991, Pubmed
Brooks, CHARMM: the biomolecular simulation program. 2009, Pubmed
Canutescu, A graph-theory algorithm for rapid protein side-chain prediction. 2003, Pubmed
Cao, Amino acid residues that control pH modulation of transport-associated current in mammalian serotonin transporters. 1998, Pubmed , Xenbase
Caplan, Molecular mechanism of ion-ion and ion-substrate coupling in the Na+-dependent leucine transporter LeuT. 2008, Pubmed
Carvelli, Dopamine transporters depolarize neurons by a channel mechanism. 2004, Pubmed
Carvelli, Dopamine transporter/syntaxin 1A interactions regulate transporter channel activity and dopaminergic synaptic transmission. 2008, Pubmed
Celik, Binding of serotonin to the human serotonin transporter. Molecular modeling and experimental validation. 2008, Pubmed
Chang, Mechanistic analyses of ion dependences in a high-affinity human serotonin transport system in transfected murine fibroblast cells. 1998, Pubmed
Chen, The third transmembrane domain of the serotonin transporter contains residues associated with substrate and cocaine binding. 1997, Pubmed
Chen, External cysteine residues in the serotonin transporter. 1997, Pubmed
Corey, A cocaine-sensitive Drosophila serotonin transporter: cloning, expression, and electrophysiological characterization. 1994, Pubmed , Xenbase
Danbolt, An [Na+ + K+]coupled L-glutamate transporter purified from rat brain is located in glial cell processes. 1992, Pubmed
Faham, The crystal structure of a sodium galactose transporter reveals mechanistic insights into Na+/sugar symport. 2008, Pubmed
Field, Transmembrane domain 6 of the human serotonin transporter contributes to an aqueously accessible binding pocket for serotonin and the psychostimulant 3,4-methylene dioxymethamphetamine. 2010, Pubmed
Fog, Calmodulin kinase II interacts with the dopamine transporter C terminus to regulate amphetamine-induced reverse transport. 2006, Pubmed
Foloppe, Stabilization of the catalytic thiolate in a mammalian glutaredoxin: structure, dynamics and electrostatics of reduced pig glutaredoxin and its mutants. 2007, Pubmed
Forrest, Identification of a chloride ion binding site in Na+/Cl -dependent transporters. 2007, Pubmed
Forrest, Mechanism for alternating access in neurotransmitter transporters. 2008, Pubmed
Galli, Patch-clamp and amperometric recordings from norepinephrine transporters: channel activity and voltage-dependent uptake. 1998, Pubmed
Henry, Serotonin and cocaine-sensitive inactivation of human serotonin transporters by methanethiosulfonates targeted to transmembrane domain I. 2003, Pubmed
Hilber, Serotonin-transporter mediated efflux: a pharmacological analysis of amphetamines and non-amphetamines. 2005, Pubmed
Hoffman, Distribution of serotonin 5-HT1C receptor mRNA in adult rat brain. 1989, Pubmed
Ingram, Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. 2002, Pubmed
Jang, Contribution of the Na-K-Cl cotransporter on GABA(A) receptor-mediated presynaptic depolarization in excitatory nerve terminals. 2001, Pubmed
Jo, CHARMM-GUI Membrane Builder for mixed bilayers and its application to yeast membranes. 2009, Pubmed
Kanai, Expression of mRNA (D2) encoding a protein involved in amino acid transport in S3 proximal tubule. 1992, Pubmed , Xenbase
Kanner, Mechanism of transport and storage of neurotransmitters. 1987, Pubmed
Kaufmann, Structural determinants of species-selective substrate recognition in human and Drosophila serotonin transporters revealed through computational docking studies. 2009, Pubmed
Li, Potential of mean force and pKa profile calculation for a lipid membrane-exposed arginine side chain. 2008, Pubmed
Lin, Single-channel currents produced by the serotonin transporter and analysis of a mutation affecting ion permeation. 1996, Pubmed , Xenbase
Lingjaerde, Uptake of serotonin in blood platelets in vitro. I. The effects of chloride. 1971, Pubmed
Mager, Measurement of transient currents from neurotransmitter transporters expressed in Xenopus oocytes. 1998, Pubmed , Xenbase
Mager, Conducting states of a mammalian serotonin transporter. 1994, Pubmed , Xenbase
Meiler, ROSETTALIGAND: protein-small molecule docking with full side-chain flexibility. 2006, Pubmed
Mitchell, Structure and function of extracellular loop 4 of the serotonin transporter as revealed by cysteine-scanning mutagenesis. 2004, Pubmed
MITCHELL, Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. 1961, Pubmed
Nelson, GABA efflux from synaptosomes: effects of membrane potential, and external GABA and cations. 1982, Pubmed
Nelson, The role of chloride ion in platelet serotonin transport. 1982, Pubmed
Ni, Evidence that NADP+ is the physiological cofactor of ADP-L-glycero-D-mannoheptose 6-epimerase. 2001, Pubmed
Noskov, Molecular mechanism of substrate specificity in the bacterial neutral amino acid transporter LeuT. 2008, Pubmed
Petersen, Ionic interactions in the Drosophila serotonin transporter identify it as a serotonin channel. 1999, Pubmed , Xenbase
Phillips, Scalable molecular dynamics with NAMD. 2005, Pubmed
Quick, Regulating the conducting states of a mammalian serotonin transporter. 2003, Pubmed , Xenbase
Ramamoorthy, Antidepressant- and cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization. 1993, Pubmed
Ramsey, Serotonin transporter function and pharmacology are sensitive to expression level: evidence for an endogenous regulatory factor. 2002, Pubmed , Xenbase
Ressl, Molecular basis of transport and regulation in the Na(+)/betaine symporter BetP. 2009, Pubmed
Schroeter, Drug targets in the embryo. Studies on the cocaine- and antidepressant-sensitive serotonin transporter. 1996, Pubmed
Screpanti, Discontinuous membrane helices in transport proteins and their correlation with function. 2007, Pubmed
Shaffer, Structure and mechanism of a Na+-independent amino acid transporter. 2009, Pubmed
Shimamura, Molecular basis of alternating access membrane transport by the sodium-hydantoin transporter Mhp1. 2010, Pubmed
Simonson, Proton binding to proteins: pK(a) calculations with explicit and implicit solvent models. 2004, Pubmed
Sonders, Multiple ionic conductances of the human dopamine transporter: the actions of dopamine and psychostimulants. 1997, Pubmed , Xenbase
Sung, Calcium-dependent interactions of the human norepinephrine transporter with syntaxin 1A. 2007, Pubmed
Swanson, Revisiting free energy calculations: a theoretical connection to MM/PBSA and direct calculation of the association free energy. 2004, Pubmed
Tavoulari, Reconstructing a chloride-binding site in a bacterial neurotransmitter transporter homologue. 2011, Pubmed
Watanabe, The mechanism of sodium and substrate release from the binding pocket of vSGLT. 2010, Pubmed
Weyand, Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter. 2008, Pubmed
Yamashita, Crystal structure of a bacterial homologue of Na+/Cl--dependent neurotransmitter transporters. 2005, Pubmed
Zhang, The cytoplasmic substrate permeation pathway of serotonin transporter. 2006, Pubmed
Zomot, Mechanism of chloride interaction with neurotransmitter:sodium symporters. 2007, Pubmed