Neurotransmitter Transporter

Neurotransmitter transporters are responsible for maintaining appropriate levels of neurotransmitters in the extracellular space and pose an avenue of potential therapeutic intervention.

From: Encyclopedia of Bones Epilepsy Research , 2009

Neurotransmitter Transporters

Aurelio Galli , ... Louis J. DeFelice , in Encyclopedia of Biological Chemistry, 2004

Reuptake

Neurotransmitter transporters operate by coupling the transmembrane translocation of substrate to the movement of driving ions downwards pre-established electrochemical gradients (cotransport). Members of this family include the membrane carriers for dopamine (DAT), serotonin (SERT), norepinephrine (NET), and γ-aminobutyric acrid (GAT1–iii). The most widely held concept of how cotransporters part is founded on the "alternating access model," in which the bounden sites for substrates and cosubstrates are alternately exposed to extracellular or cytoplasmic environments via conformational changes in the transporter poly peptide. The thermodynamic work of the transporter is accomplished by coupling the flux of substrate to the movement of cotransported ions downward their electrochemical gradients. The stoichiometry inferred from radiolabeled transport studies on neurotransmitter transporter-expressing cells and membrane vesicles is ii Na+, 1 Cl−, and ane molecule of substrate for DAT and GAT1. For NET the proposed stoichiometry is one Na+, ane Cl−, and one molecule of NE. With the exception of mammalian SERT, which is proposed to be electroneutral due to additional counter ion menses, the neurotransmitter transporter process is electrogenic pregnant that the send bicycle moves internet charges across the plasma membrane. Indeed, in cell lines stably transfected with the cDNA of neurotransmitter transporters, it is possible to tape electric currents generated by their activity using the patch clench technique in the whole-jail cell configuration. However, these currents are by and large besides large to be explained entirely by fixed stoichiometry models (see Figure 1) .

Figure 1. Model for neurotransmitter transporter function.

Recent electrophysiological studies of both native and cloned neurotransmitter transporters revealed that transporters can take cursory and rare channel-like openings comparable to those generated by ligand-gated ion channels. Models for this exiting style of the neurotransmitter transporters have been established, in which substrate, Na+ and Cl− induce the carrier to transport in the alternate access mode (Figure 1A, 1B), and rarely switching to a channel-like mode (Figure 1C). The alternating access model assumes that the substrate permeation occurs through a state transition (A↔B) and results in the send of a unmarried neurotransmitter molecule (Figures 1A and 1B). The aqueduct-like mode (Effigy 1C) is a low probability consequence that consists of hundreds of ions crossing the membrane (using a transporter pore), down their electrochemical gradients. These models accept been recently refined and expanded based on new data.

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Neurotransmitter Transporters

K. Erreger , ... C. Saunders , in Encyclopedia of Biological Chemistry (2d Edition), 2013

Reuptake and Electrogenicity

Neurotransmitter transporters operate by coupling the transmembrane translocation of substrate to the movement of driving ions down pre-established electrochemical gradients (co-send). Members of the SLC6 family include the DA transporter (DAT), 5HT transporter (SERT), NE transporter (Cyberspace), and GABA transporter (e.g., GAT1) that are dependent on both extracellular sodium (Na +) and chloride (Cl−) to function, whereas the glutamate transporters (EAATs) depend on extracellular Na+ and intracellular potassium (G+). Both families of transporters use the Na+ gradient generated by high extracellular Na+ and low intracellular Na+ to drive uptake of neurotransmitter into cells. The most widely held concept of how co-transporters role is founded on the alternating admission model, in which the bounden sites for substrates and ions are alternately exposed to extracellular or cytoplasmic environments via conformational changes in the transporter protein. The thermodynamic work of the transporter is accomplished by coupling the flux of substrate to the motility of co-transported ions down their electrochemical gradients. The exact stoichiometry of ions depends on the transporter and tin even exist modulated by regulatory proteins. The neurotransmitter transporter process is electrogenic, significant that the send procedure moves net charges across the plasma membrane due to the move of ions accompanying the movement of the neurotransmitter. Indeed, in both heterologous cell lines expressing transporters and in native neurons in cell civilisation, electrical currents generated by transporters take been reported. In addition to the stoichiometric current due to motion of ions coupled to neurotransmitter transporters, electric current that is independent of, or uncoupled from, neurotransmitter movement has been reported through transporters. Particularly notable are the relatively large Cl− currents through the glutamate transporters, although uncoupled currents are besides known for the monoamine transporters including DAT. These uncoupled currents through the transporters are big enough in magnitude to alter neuronal membrane potential and excitability.

Recent electrophysiological studies of both native and cloned neurotransmitter transporters revealed that they have cursory and rare aqueduct-like openings comparable to those generated by ligand-gated ion channels. Models for this exiting mode of the neurotransmitter transporters have been established, in which substrate and ions induce the carrier to transport in the alternating access style ( Figures i(a) and 1(b) ), and rarely switch to a channel-similar style ( Figure 1(c) ). The alternating admission model assumes that the substrate permeation occurs through a state transition (A↔B) and results in the transport of a single neurotransmitter molecule ( Figures 1(a) and 1(b) ). The channel-similar mode ( Figure one(c) ) is a low-probability event that consists of hundreds of ions crossing the membrane (using the transporter aqueous pore) down their electrochemical gradients.

Figure i. Model for neurotransmitter transporters function. S indicates a substrate molecule and the ruby circles depict a co-transported ion. The conformational switch between A and B is the classical alternating admission model of co-transport. C represents the channel-similar conformation that allows rapid bursts of ions and/or substrates to movement across the membrane.

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Ion Channels of Excitable Cells

Michael W. Quick , Henry A. Lester , in Methods in Neurosciences, 1994

Flux Measurements

Studies of neurotransmitter transporters in our laboratory ( 18, xix) are performed past measuring the uptake of [3H] neurotransmitters in transporter mRNA-injected oocytes. The oocytes are preincubated at room temperature in ND96 for 15 min. A standard pipetter (in which the disposable xanthous tip has been cut to a sufficient diameter for easy withdrawal of an oocyte) is used to transfer the oocytes along with twoscore µl of ND96 to individual wells of a 96-well microtiter plate. To each well, 10 µl of the reaction buffer is added. For a typical γ-aminobutyric acid (GABA) uptake assay, the reaction buffer for one oocyte contains 5 µl 2× ND96, four µl distilled h2o, and ane µl [3H]GABA (1 µCi/µl, NEN DuPont, Boston MA). The reaction buffer should be added in timed intervals to maintain constant uptake time. After the desired uptake fourth dimension, the reaction is terminated past (i) the rapid addition of 200/µl ND96 to the microtiter well and (ii) the immediate removal of the oocyte. Each oocyte is passed through four washes of ND96 and then placed in a 7-ml copolymer plastic scintillation vial (Research Products Intl., Mount Prospect, IL, Model 125508) containing 500 µl 10% SDS. The oocyte is solubilized (approximately 45 min) at 42°C in a rotating water bath (New Brunswick Scientific, Edison, NJ, Model G76). Approximately 3 ml of water-compatible scintillation cocktail is and so added to the vial and the amount of uptake is determined by scintillation counter.

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Excitatory Amino Acrid Transporters in Neurons and Glia☆

S. Underhill , in Reference Module in Biomedical Sciences, 2014

Summary and Future Directions

The EAAT family of neurotransmitter transporters plays an of import and dynamic role in the brain. From recycling glutamate, to maintaining low extracellular glutamate concentrations to even more precise actions of maintaining synaptic specificity, EAATs are an important component of the synaptic structure. Electric current studies are addressing the precise regulation of expression and localization of these carriers at the plasma membrane during development, in synaptic modulation involved in learning and in dysregulation of these transporters in pathophysiological states. A clearer understanding of the structure of the EAATs and the roles of the currents carried by the EAATs will help to farther resolve the part of these transporters in the brain.

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Genes Associated with Alcohol Withdrawal

Kesheng Wang PhD , Liang Wang MD, PhD, MPH , in Molecular Aspects of Alcohol and Diet, 2016

SLC6A4

Solute carrier family vi (neurotransmitter transporter), member 4 (SLC6A4) factor (also known equally HTT; 5HTT; OCD1; SERT; five-HTT; SERT1; HSERT; five-HTTLPR) is a neurotransmitter in the central and peripheral nervous systems. By somatic cell hybrid and in situ hybridization studies, Ramamoorthy et al. mapped a single gene encoding the human 5-HT transporter to chromosome 17q11.one-q12. 125 Feinn et al. conducted a meta-analysis of the clan of the functional serotonin transporter promoter polymorphism with Advertisement. 126 One study investigated the association of one 5-HTTLPR polymorphism with obsessive-compulsive alcohol craving in 124 male Caucasian patients admitted for booze detoxification treatment. The results suggests that the 5-HTTLPR polymorphism was associated with college compulsive alcohol craving at the starting time of alcohol withdrawal. 42

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Neurotransmitter Transporters and Their Function in the Pharmacological Actions of Therapeutic and Abused Drugs

Nikki J. Clauss , Lynette C. Daws , in Reference Module in Biomedical Sciences, 2021

ii.1 Location

It was originally thought that these NTTs were located in the synaptic cleft, but electron microscopy studies subsequently showed them to be located extrasynptically (e.g., Pickel and Chan, 1999; Kristensen et al., 2011) (Fig. iA ). The extrasynaptic location of these NTTs implies that signaling occurs via paracrine (volume) manual (meet Fuxe et al., 2007; Borroto-Escuela et al., 2021). SERT, Cyberspace and DAT are located predominantly on dendrites and axons throughout brain, with their expression levels closely mapping to the location of their cognate neurotransmitter systems. These transporters are located primarily on neurons of their related neurotransmitter, with expression existence more sparse on not-cognate neurons and glia. Expression patterns of GATs and GlyTs are more complex, varying in density throughout brain in both neurons and astrocytes. OCT3 and PMAT, located on neurons and glia, are broadly distributed in encephalon, oftentimes most densely in regions with high monoamine innervation. OCT1 and OCT2 are less widely expressed in encephalon. CNS distribution of these transporters is described in more item in afterwards sections.

Fig. 1

Fig. one. Role of SLC6 neurotransmitter transporters (NTTs) in synaptic manual. (A) Schematic representation of monoaminergic, GABAergic, and glycinergic synaptic terminals. In the presynaptic terminals of monoaminergic neurons, vesicular monoamine transporters (VMATs) belonging to the SLC18 cistron family (Eiden et al., 2004) sequester 5-HT, DA, and NE into synaptic vesicles, whereas the vesicular inhibitory amino acid transporters (VIAATs) belonging to the SLC32 factor family (Gasnier, 2004) sequester GABA and glycine into synaptic vesicles in GABAergic and glycinergic neurons, respectively. Afterwards vesicular release, neurotransmitters exert their effects on post- and presynaptic receptors. The SLC6 NTTs are crucial for termination of neurotransmission by performing reuptake of the neurotransmitters from the synaptic crack into presynaptic terminals or glial cells likewise as for maintaining depression tonic neurotransmitter concentrations outside synapses. The monoamine transporters (SERT, NET, and DAT) are localized to extrasynaptic sites (Torres et al., 2003), and to a lesser extent, glia (Inazu et al., 2001; Pickel and Chan, 1999) so are not shown here, whereas GATs and GlyTs are localized to synaptic and extrasynaptic sites in improver to glial cells (Supplisson and Roux, 2002; Conti et al., 2004; Madsen et al., 2010). (B) Chemical structures of the endogenous substrates for SLC6 NTTs and ion coupling stoichiometry for neurotransmitter reuptake.

 Reproduced with permission, from Kristensen Equally, Andersen J, Jørgensen TN, Sørensen L, Eriksen J, Loland CJ, Strømgaard Yard, Gether U (2011) SLC6 neurotransmitter transporters: Construction, role, and regulation. Pharmacological Reviews 63(3): 585–640. PMID: 21752877, doi: https://doi.org/10.1124/pr.108.000869.

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Membrane Trafficking of Vesicular Neurotransmitter Transporters

ROBERT T. FREMEAU JR. , ROBERT H. EDWARDS , in Protein Trafficking in Neurons, 2007

I INTRODUCTION

Much of the current interest in neurotransmitter transporters derives from their original identification every bit the sites of action for multiple psychoactive drugs. Cocaine acts by inhibiting the reuptake of monoamine transmitters across the plasma membrane ( Axelrod et al. 1961). Inhibition of the dopamine transporter (DAT) may be virtually important, but recent work also has suggested that cocaine tin act by inhibiting the serotonin transporter (SERT) and possibly the norepinephrine transporter (Giros et al. 1996; Rocha et al. 1998; Sora et al. 2001; Moron et al. 2002). Tricyclic antidepressants inhibit norepinephrine reuptake and the more recent serotonin-selective reuptake inhibitors (SSRIs) specifically target SERT (Amara and Kuhar 1993). Methamphetamine acts past promoting flux reversal mediated by DAT, and MDMA ("Ecstasy") by promoting efflux through SERT (Rudnick and Wall 1992a; Sulzer et al. 1995). Withal, the power of amphetamines to release monoamines through this nonvesicular mechanism depends in role on the storage of monoamine in secretory vesicles. Amphetamines deed as weak bases to dissipate the proton electrochemical gradient that drives transport across the vesicle membrane, assuasive the efflux of stored monoamine into the cytoplasm before reverse transport across the plasma membrane (Sulzer and Rayport 1990; Sulzer et al. 1995; Fon et al. 1997). Thus, amphetamines also act indirectly to interfere with vesicular monoamine transport.

The pronounced psychoactive effects of cocaine, antidepressants, and amphetamines signal the potential for regulation of neurotransmitter send to influence normal behavior and contribute to neuropsychiatric disease. Many groups take studied the regulation of neurotransmitter transport. A number of neurotransmitter transporters undergo phosphorylation, but the physiological consequences of this posttranslational modification remains uncertain. In the example of the dopamine transporter, phosphorylation of the Nterminus was identified several years ago (Vaughan et al. 1997), just only recently has been shown to affect send activity. Northward-terminal phosphorylation increases the rate of efflux mediated by DAT—uptake is not afflicted—and this contributes to the efflux of dopamine produced by amphetamines, through a channel-similar mechanism (Gnegy et al. 2004; Khoshbouei et al. 2004; Kahlig et al. 2005). A number of other neurotransmitter transporters as well undergo phosphorylation. Phosphorylation of the GABA transporter GAT1 by poly peptide kinase C (PKC) influences its ability to be modulated by the t-SNARE syntaxin 1A (Beckman et al. 1998). In many cases, still, phosphorylation affects trafficking rather than ship activity. Indeed, changes in membrane trafficking remain among the bestunderstood mechanisms that regulate neurotransmitter ship.

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Posttraumatic Stress Disorder

G.H. Wynn , ... R. Ursano , in Conn's Translational Neuroscience, 2017

SLC6A3

The SLC6A3 (solute carrier family 6 (neurotransmitter transporter, dopamine), fellow member 3) locus increases risk of PTSD. 9R allele carriers had virtually double the risk of lifetime PTSD compared to 10R/10R genotype carriers, controlling for age, sex activity, race, socioeconomic status, number of traumas, smoking, and lifetime depression. In the subsample of participants with available methylation data, a significant interaction was observed whereby 9R allele carriers showed an increased risk of lifetime PTSD only in conjunction with high methylation in the SLC6A3 promoter locus, decision-making for the same covariates. These data indicate a role for the 9R allele in increasing susceptibility to PTSD and provide preliminary testify that a "double hit" model, including both a putatively reduced office allele and high methylation in the promoter region, may more accurately capture molecular take a chance of PTSD at the SLC6A3 locus.

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Neuroglia, Overview

Angus M. Brown , Bruce R. Bribe , in Encyclopedia of the Human being Brain, 2002

III.D Physiology

The membrane of astrocytes contains a variety of neurotransmitter transporters, ion channels, and gap junctions. The neurotransmitter transporters act to articulate the ECS of neurotransmitters, which accrue during electrical activity. The continued presence of neurotransmitters in the ECS could lead to prison cell decease by increased intracellular Ca 2+, e.thousand., glutamate. Alternatively, the sustained presence of GABA may atomic number 82 to prolonged inhibition of cells. Astrocytes also comprise a variety of ion channels. Although Na+ channels are nowadays, they are not present in sufficient density relative to K+ channels to crusade action potentials. Multiple Grand+ channels are nowadays and because astrocytes are almost exclusively permeable to K+ at residue, they act every bit K+ electrodes and the resting membrane potential is dictated about exclusively by the transmembrane concentration of K+ ions. As such, astrocytes are exquisitely sensitive to changes in extracellular K+ concentration, and changes in this concentration due to increased neuronal activity are immediately sensed by astrocytes. Astrocytes likewise contain Catwo+ channels, but there has been controversy virtually whether Catwo+ channels are present in vivo. In cultured astrocytes and in astrocytes studied after having undergone trauma, Ca2+ channels have been shown to be present. Withal, i study could observe no evidence of Ca2+ channels nowadays in vitro, suggesting instead that increased intracellular Ca2+ occurred due to the activation of metabotropic glutamate receptors. These data suggested that the presence of Ca2+ channels in previous studies was due to up-regulation of Ca2+ channel expression induced by culture conditions or injury. Still, technical limitations take made answering this question difficult. Patch clamp recordings suffer from the effects of space clamp induced by the gap junctional dissipation of current. However, a study using electrophysiological techniques and antibodies directed at Catwo+ channel subunits indicated that nifedipine-sensitive L-type Ca2+ channels are present on both astrocytes and axons in the developed rat optic nervus.

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Clinically Of import Hormone Effects on Brain and Beliefs

Brian Reed , Mary Jeanne Kreek , in Hormones, Encephalon and Beliefs (Third Edition), 2017

4.21.ane.iv Cocaine and the Monoamine Neurotransmitter Systems

The most potent binding sites of cocaine are the monoamine neurotransmitter transporters, the dopamine transporter (DAT), the serotonin transporter (SERT, aka 5HTT, 5-hydroxytryptamine transporter), and norepinephrine transporter (NET), each of which serves to remove the corresponding neurotransmitter from the synapse, thereby facilitating the termination of neurotransmitter signaling ( Blakely and Bauman, 2000). At each of these three transporters, cocaine acts as an inhibitor, preventing clearance and resulting in enhanced signaling. The monoaminergic systems serve to regulate diverse endocrine systems, both straight and indirectly, and the effects of cocaine (and of other psychostimulants such as the amphetamines, non covered explicitly herein) on hormone levels are consistent to this regulation (e.thousand., Borowsky and Kuhn, 1991).

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