Vesicular and Plasma Membrane Transporters for Neurotransmitters

Blakely, Randy D.; Edwards, Robert H.

doi:10.1101/cshperspect.a005595

Cited by 143 publications

(132 citation statements)

References 252 publications

(201 reference statements)

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“…As such, the genetic removal of plasmic transporters for DA, 26 5-HT 27 and NE 28 has provided animal models with increased transmission, which enabled many important findings in recent years. 4,5 The targeted deletion of the monoamine vesicular transporter has now enabled us to engineer mice with the opposite phenotype: a constitutive decrease (or even absence) of the releasable monoamine pool ( Table 1).…”

Section: Discussionmentioning

confidence: 99%

“…The plasma membrane transporters (norepinephrine transporter [NET], serotonin transporter [SERT] and dopamine transporter [DAT]) play an essential role in the clearance and recycling of monoamines via uptake from the extracellular space, and the vesicular monoamine transporter (VMAT) accumulates monoamines in synaptic vesicles and is essential for their release. 5 Two VMAT genes have been cloned, 6,7 and although the proteins encoded by these genes are structurally related, they fulfill distinct roles. VMAT1 is primarily expressed in the peripheral nervous system; VMAT2 is primarily expressed in the neurons of the central nervous system.…”

Section: Introductionmentioning

confidence: 99%

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Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Isingrini¹,

Perret²,

Rainer³

et al. 2016

jpn

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IntroductionMonoaminergic neurotransmitters, namely dopamine (DA), noradrenaline (NE) and serotonin (5-HT), extensively modulate cognitive, affective, neuroendocrine and motor functions in the brain. 1 The role of the monoaminergic systems in psychi atric pathology has been clearly established based on the observation that effective psychotropic drugs primarily target these systems. [2][3][4] However, the functional subdivision of the monoamine systems indicates a disparity in cerebral distribution, receptor subtypes and mechanisms of action. Unravelling the independent roles of the monoaminergic systems in patients with neuropsychiatric disorders remains a challenge that is complicated by their large anatomic, pharmacological and functional overlaps.At the molecular level, the monoaminergic systems share common properties. The intra-and extracellular concentrations of monoamines are primarily controlled by 2 types of transporters. The plasma membrane transporters (norepinephrine transporter [NET], serotonin transporter [SERT] and dopamine transporter [DAT]) play an essential role in the clearance and recycling of monoamines via uptake from the extracellular space, and the vesicular monoamine transporter (VMAT) accumulates monoamines in synaptic vesicles and is essential for their release. 5 Two VMAT genes have been cloned, 6,7 and although the proteins encoded by these genes are structurally related, they fulfill distinct roles. VMAT1 is primarily expressed in the peripheral nervous system; VMAT2 is primarily expressed in the neurons of the central nervous system. 8,9 The functions of VMAT2 include storage of monoamines, protection of monoamines from cytoplasmic oxi dation and regulation of stimulated monoamine quantal release. 10 Thus, VMAT2 deficiency contributes to a decrease in the synaptic release of monoamines and an increase in the degradation of intracellular monoamines.To better understand the physiologic and behavioural roles of monoaminergic signalling, several investigators have created VMAT2-knockout (KO) mice by disrupting the gene that Background:The monoaminergic transmitters dopamine (DA), noradrenaline (NE) and serotonin (5-HT) modulate cerebral functions via their extensive effects in the brain. Investigating their roles has led to the creation of vesicular monoaminergic transporter-2 (VMAT2) knockout (KO) mice. While this mutation results in postnatal death, VMAT2-heterozygous (HET) mice are viable and show a complex behavioural phenotype. However, the simultaneous alteration of the 3 systems prevents investigations into their individual functions. Methods: To assess the specific role of NE, 5-HT and DA, we genetically disrupted their neurotransmission by creating conditional VMAT2-KO mice with targeted recombination. These specific recombinations were obtained by breeding VMAT2 lox/lox mice with DBHcre, SERTcre and DATcre mice, respectively. We conducted a complete neurochemical and behavioural characterization of VMAT2-HET animals in each system. Results: Conditional VMAT2-KO mice reveale...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Isingrini¹,

Perret²,

Rainer³

et al. 2016

jpn

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“…Vesicular transporters of cationic neurotransmitters include the vesicular monoamine transporters (VMATs) and acetylcholine transporter (5,6). Two monoamine transporters, VMAT1 and VMAT2, are responsible for the uptake of dopamine, serotonin, adrenaline, noradrenaline, and histamine in a process that involves the exchange of two protons for one substrate molecule (1)(2)(3)7).…”

mentioning

confidence: 99%

“…Transport and storage of neurotransmitters in secretory vesicles, mediated by vesicular neurotransmitter transporters, allow the regulated exocytosis of neurotransmitters to the synaptic cleft (1)(2)(3)(4). Vesicular transporters of cationic neurotransmitters include the vesicular monoamine transporters (VMATs) and acetylcholine transporter (5,6).…”

mentioning

confidence: 99%

Emulating proton-induced conformational changes in the vesicular monoamine transporter VMAT2 by mutagenesis

Yaffe

Vergara-Jaque

Forrest

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransporters located in synaptic vesicles are essential for communication between nerve cells in a process mediated by neurotransmitters. Vesicular monoamine transporter (VMAT), a member of the largest superfamily of transporters, mediates transport of monoamines to synaptic vesicles and storage organelles in a process that involves exchange of two H + per substrate. VMAT transport is inhibited by the competitive inhibitor reserpine, a second-line agent to treat hypertension, and by the noncompetitive inhibitor tetrabenazine, presently in use for symptomatic treatment of hyperkinetic disorders. During the transport cycle, VMAT is expected to occupy at least three different conformations: cytoplasm-facing, occluded, and lumen-facing. The lumen-to cytoplasm-facing transition, facilitated by protonation of at least one of the essential membrane-embedded carboxyls, generates a binding site for reserpine. Here we have identified residues in the cytoplasmic gate and show that mutations that disrupt the interactions in this gate also shift the equilibrium toward the cytoplasm-facing conformation, emulating the effect of protonation. These experiments provide significant insight into the role of proton translocation in the conformational dynamics of a mammalian H + -coupled antiporter, and also identify key aspects of the mode of action and binding of two potent inhibitors of VMAT2: reserpine binds the cytoplasm-facing conformation, and tetrabenazine binds the lumen-facing conformation.neurotransmitter transporter | ion coupling | reserpine | tetrabenazine

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“…In mammals, the vesicular monoamine transporters (VMAT1/SLC18A1; VMAT2/SLC18A2) store newly synthesized dopamine, serotonin and adrenaline/noradrenaline in synaptic vesicles and large dense core vesicles for their ensuing synaptic and extra-synaptic release [33]. Drosophila has only one vesicular monoamine transporter (dVMAT) gene, which produces two splice variants with distinct C-termini, dVMAT-A and dVMAT-B [34]: dVMAT-A is expressed in dopaminergic, octopaminergic and serotonergic neurons [34].…”

Section: The Dopaminergic Systemmentioning

confidence: 99%

Big Lessons from Tiny Flies:<em> Drosophila Melanogaster </em>as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems

Kasture

Hummel

Sučić

et al. 2018

Preprint

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The brain of Drosophila melanogaster is comprised of some 100,00 neurons, 127 and 80 of which are dopaminergic and serotonergic, respectively. Their activity regulates behavioral functions equivalent to those in mammals, e.g. motor activity, reward and aversion, memory formation, feeding, sexual appetite etc. Mammalian dopaminergic and serotonergic neurons are known to be heterogeneous. They differ in their projections and in their gene expression profile. A sophisticated genetic tool box is available, which allows for targeting virtually any gene with amazing precision in Drosophila melanogaster. Similarly, Drosophila genes can be replaced by their human orthologs including disease-associated alleles. Finally, genetic manipulation can be restricted to single fly neurons. This has allowed for addressing the role of individual neurons in circuits, which determine attraction and aversion, sleep and arousal, odor preference etc. Flies harboring mutated human orthologs provide models, which can be interrogated to understand the effect of the mutant protein on cell fate and neuronal connectivity. These models are also useful for proof-of-concept studies to examine the corrective action of therapeutic strategies. Finally, experiments in Drosophila can be readily scaled up to an extent, which allows for drug screening with reasonably high throughput.

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Vesicular and Plasma Membrane Transporters for Neurotransmitters

Cited by 143 publications

References 252 publications

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Selective genetic disruption of dopaminergic, serotonergic and noradrenergic neurotransmission: insights into motor, emotional and addictive behaviour

Emulating proton-induced conformational changes in the vesicular monoamine transporter VMAT2 by mutagenesis

Big Lessons from Tiny Flies:<em> Drosophila Melanogaster </em>as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems

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