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Joanne Wang - One of the best experts on this subject based on the ideXlab platform.

  • brain plasma membrane Monoamine Transporter in health and disease
    Handbook of experimental pharmacology, 2021
    Co-Authors: Leticia S Vieira, Joanne Wang
    Abstract:

    Precise control of Monoamine neurotransmitter levels in the central nervous system (CNS) is crucial for proper brain function. Dysfunctional Monoamine signaling is associated with several neuropsychiatric and neurodegenerative disorders. The plasma membrane Monoamine Transporter (PMAT) is a new polyspecific organic cation Transporter encoded by the SLC29A4 gene. Capable of transporting Monoamine neurotransmitters with low affinity and high capacity, PMAT represents a major uptake2 Transporter in the brain. Broadly expressed in multiple brain regions, PMAT can complement the high-affinity, low-capacity Monoamine uptake mediated by uptake1 Transporters, the serotonin, dopamine, and norepinephrine Transporters (SERT, DAT, and NET, respectively). This chapter provides an overview of the molecular and functional characteristics of PMAT together with its regional and cell-type specific expression in the mammalian brain. The physiological functions of PMAT in brain Monoamine homeostasis are evaluated in light of its unique transport kinetics and brain location, and in comparison with uptake1 and other uptake2 Transporters (e.g., OCT3) along with corroborating experimental evidences. Lastly, the possibility of PMAT's involvement in brain pathophysiological processes, such as autism, depression, and Parkinson's disease, is discussed in the context of disease pathology and potential link to aberrant Monoamine pathways.

  • interspecies comparison of the functional characteristics of plasma membrane Monoamine Transporter pmat between human rat and mouse
    Journal of Chemical Neuroanatomy, 2017
    Co-Authors: Yoshiyuki Shirasaka, Haichuan Duan, Nora Lee, Joanna Pak, Joanne Wang
    Abstract:

    Plasma membrane Monoamine Transporter (PMAT) is a newly discovered Monoamine Transporter belonging to the equilibrative nucleoside Transporter family. Highly expressed in the brain, PMAT represents a major uptake2 Transporter that may play a role in Monoamine clearance. Although human PMAT has been functionally characterized at the molecular level, rodent models are often used to evaluate PMAT function in ex vivo and in vivo studies. The aim of this study was to examine if there is potential species difference in the functional characteristics of PMAT between human, rat and mouse. A set of transfected cells stably expressing human PMAT (MDCK/hPMAT), rat Pmat (MDCK/rPmat) and mouse Pmat (Flp293/mPmat) were constructed. In MDCK/hPMAT, MDCK/rPmat and Flp293/mPmat cells, cellular localization analyses revealed that hPMAT, rPmat and mPmat are expressed and mainly localized to the plasma membranes of cells. The uptake of MPP+, serotonin and dopamine by MDCK/hPMAT, MDCK/rPmat and Flp293/mPmat cells was significantly increased compared with those by the mock transfection control. In contrast, two nucleosides, uridine and adenosine, minimally interacted with PMAT/Pmat in all species. The hPMAT-, rPmat- and mPmat-mediated uptakes of MPP+, serotonin and dopamine were saturable, with Km values of 33.7μM, 70.2μM and 49.5μM (MPP+), 116μM, 82.9μM and 231μM (serotonin), and 201μM, 271μM and 466μM (dopamine), respectively, suggesting similar substrate affinities between human and rodent PMAT/Pmat. The prototypical inhibitors, decynium 22 and GBR12935, also showed similar inhibition potencies between species. In conclusion, the present study demonstrated interspecies similarities in the functional characteristics of human and rodent PMAT/Pmat, which indicate a practical utility of rat and mouse animal models for further investigating and extrapolating the in vivo function of PMAT in humans.

  • potent and selective inhibition of plasma membrane Monoamine Transporter by hiv protease inhibitors
    Drug Metabolism and Disposition, 2015
    Co-Authors: Haichuan Duan, Robert S Foti, Yongmei Pan, Peter W Swaan, Joanne Wang
    Abstract:

    Plasma membrane Monoamine Transporter (PMAT) is a major uptake-2 Monoamine Transporter that shares extensive substrate and inhibitor overlap with organic cation Transporters 1-3 (OCT1-3). Currently, there are no PMAT-specific inhibitors available that can be used in in vitro and in vivo studies to differentiate between PMAT and OCT activities. In this study, we showed that IDT307 (4-(4-(dimethylamino)phenyl)-1-methylpyridinium iodide), a fluorescent analog of 1-methyl-4-phenylpyridinium (MPP+), is a transportable substrate for PMAT and that IDT307-based fluorescence assay can be used to rapidly identify and characterize PMAT inhibitors. Using the fluorescent substrate-based assays, we analyzed the interactions of eight human immunodeficiency virus (HIV) protease inhibitors (PIs) with human PMAT and OCT1-3 in human embryonic kidney 293 (HEK293) cells stably transfected with individual Transporters. Our data revealed that PMAT and OCTs exhibit distinct sensitivity and inhibition patterns toward HIV PIs. PMAT is most sensitive to PI inhibition whereas OCT2 and OCT3 are resistant. OCT1 showed an intermediate sensitivity and a distinct inhibition profile from PMAT. Importantly, lopinavir is a potent PMAT inhibitor and exhibited >120 fold selectivity toward PMAT (IC₅₀ = 1.4 ± 0.2 µM) over OCT1 (IC₅₀ = 174 ± 40 µM). Lopinavir has no inhibitory effect on OCT2 or OCT3 at maximal tested concentrations. Lopinavir also exhibited no or much weaker interactions with uptake-1 Monoamine Transporters. Together, our results reveal that PMAT and OCTs have distinct specificity exemplified by their differential interaction with HIV PIs. Further, we demonstrate that lopinavir can be used as a selective PMAT inhibitor to differentiate PMAT-mediated Monoamine and organic cation transport from those mediated by OCT1-3.

  • electrophysiological characterization of the polyspecific organic cation Transporter plasma membrane Monoamine Transporter
    Drug Metabolism and Disposition, 2012
    Co-Authors: Shiro Itagaki, Mingyan Zhou, Vadivel Ganapathy, Ellappan Babu, Joanne Wang
    Abstract:

    Plasma membrane Monoamine Transporter (PMAT) is a polyspecific organic cation (OC) Transporter that transports a variety of endogenous biogenic amines and xenobiotic cations. Previous radiotracer uptake studies showed that PMAT-mediated OC transport is sensitive to changes in membrane potential and extracellular pH, but the precise role of membrane potential and protons on PMAT-mediated OC transport is unknown. Here, we characterized the electrophysiological properties of PMAT in Xenopus laevis oocytes using a two-microelectrode voltage-clamp approach. PMAT-mediated histamine uptake is associated with inward currents under voltage-clamp conditions, and the currents increased in magnitude as the holding membrane potential became more negative. A similar effect was also observed for another cation, nicotine. Substrate-induced currents were largely independent of Na+ but showed strong dependence on membrane potential and pH of the perfusate. Detailed kinetic analysis of histamine uptake revealed that the energizing effect of membrane potentials on PMAT transport is mainly due to an augmentation of Imax with little effect on K0.5. At most holding membrane potentials, Imax at pH 6.0 is approximately 3- to 4-fold higher than that at pH 7.5, whereas K0.5 is not dependent on pH. Together, these data unequivocally demonstrate PMAT as an electrogenic Transporter and establish the physiological inside-negative membrane potential as a driving force for PMAT-mediated OC transport. The important role of membrane potential and pH in modulating the transport activity of PMAT toward OCs suggests that the in vivo activity of PMAT could be regulated by pathophysiological processes that alter physiological pH or membrane potential.

  • Tyrosine 112 is Essential for Organic Cation Transport by the Plasma Membrane Monoamine Transporter
    Biochemistry, 2010
    Co-Authors: Joanne Wang
    Abstract:

    Plasma membrane Monoamine Transporter (PMAT) is a polyspecific organic cation Transporter in the solute carrier 29 (SLC29) family. Previous studies suggested that the major substrate recognition sites are located within transmembrane domains (TM) 1-6, and interaction of PMAT with organic cations may involve aromatic residues. In this study, we analyzed the roles of tyrosine and tryptophan residues located within TM1-6 with a goal of identifying potential residues involved in substrate recognition and translocation. The six tyrosines and one tryptophan in this region were each mutated to alanine followed by analysis of the mutant's membrane localization and transport activity toward 1-methyl-4-phenylpyridinium (MPP(+)), serotonin (5-HT), and dopamine. Two mutants, Y85A and Y112A, exhibited normal cell surface expressions but lost their transport activities toward organic cations. At position Y85, aromatic substitution with phenylalanine or tryptophan fully restored organic cation transport activity. Interestingly, at position Y112, phenylalanine substitution was not allowed. Tryptophan substitution at Y112 partially restored transport activity toward 5-HT and dopamine but severely impaired MPP(+) transport. Detailed kinetic analyses revealed that tryptophan substitution at Y85 and Y112 affected the apparent binding affinity (K(m)) and maximal transport velocity (V(max)) in a substrate-dependent manner. Together, our data suggest that Y85 and Y112 are important molecular determinants for PMAT function, and Y112 is indispensable for optimal interaction with organic cation substrates. Our analyses also suggest the involvement of transmembrane domains 1 and 2 in forming the substrate permeation pathway of PMAT.

Gary W Miller - One of the best experts on this subject based on the ideXlab platform.

  • vesicular Monoamine Transporter 2 vmat2 level regulates mptp vulnerability and clearance of excess dopamine in mouse striatal terminals
    Toxicological Sciences, 2016
    Co-Authors: Kelly M Lohr, Amy R Dunn, Kristen A Stout, Carlie A Hoffman, Alison I Bernstein, Minzheng Wang, Merry Chen, Miranda J Mcdaniel, Gary W Miller
    Abstract:

    The vesicular Monoamine Transporter 2 (VMAT2) packages neurotransmitters for release during neurotransmission and sequesters toxicants into vesicles to prevent neuronal damage. In mice, low VMAT2 levels causes catecholaminergic cell loss and behaviors resembling Parkinson's disease, while high levels of VMAT2 increase dopamine release and protect against dopaminergic toxicants. However, comparisons across these VMAT2 mouse genotypes were impossible due to the differing genetic background strains of the animals. Following back-crossing to a C57BL/6 line, we confirmed that mice with approximately 95% lower VMAT2 levels compared with wild-type (VMAT2-LO) display significantly reduced vesicular uptake, progressive dopaminergic terminal loss with aging, and exacerbated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Conversely, VMAT2-overexpressing mice (VMAT2-HI) are protected from the loss of striatal terminals following MPTP treatment. We also provide evidence that enhanced vesicular filling in the VMAT2-HI mice modifies the handling of newly synthesized dopamine, indicated by changes in indirect measures of extracellular dopamine clearance. These results confirm the role of VMAT2 in the protection of vulnerable nigrostriatal dopamine neurons and may also provide new insight into the side effects of L-DOPA treatments in Parkinson's disease.

  • increased vesicular Monoamine Transporter 2 vmat2 slc18a2 protects against methamphetamine toxicity
    ACS Chemical Neuroscience, 2015
    Co-Authors: Kelly M Lohr, Amy R Dunn, Kristen A Stout, Minzheng Wang, Thomas S Guillot, Ali Salahpour, Gary W Miller
    Abstract:

    The psychostimulant methamphetamine (METH) is highly addictive and neurotoxic to dopamine terminals. METH toxicity has been suggested to be due to the release and accumulation of dopamine in the cytosol of these terminals. The vesicular Monoamine Transporter 2 (VMAT2; SLC18A2) is a critical mediator of dopamine handling. Mice overexpressing VMAT2 (VMAT2-HI) have an increased vesicular capacity to store dopamine, thus augmenting striatal dopamine levels and dopamine release in the striatum. Based on the altered compartmentalization of intracellular dopamine in the VMAT2-HI mice, we assessed whether enhanced vesicular function was capable of reducing METH-induced damage to the striatal dopamine system. While wildtype mice show significant losses in striatal levels of the dopamine Transporter (65% loss) and tyrosine hydroxylase (46% loss) following a 4 × 10 mg/kg METH dosing regimen, VMAT2-HI mice were protected from this damage. VMAT2-HI mice were also spared from the inflammatory response that follows METH treatment, showing an increase in astroglial markers that was approximately one-third of that of wildtype animals (117% vs 36% increase in GFAP, wildtype vs VMAT2-HI). Further analysis also showed that elevated VMAT2 level does not alter the ability of METH to increase core body temperature, a mechanism integral to the toxicity of the drug. Finally, the VMAT2-HI mice showed no difference from wildtype littermates on both METH-induced conditioned place preference and in METH-induced locomotor activity (1 mg/kg METH). These results demonstrate that elevated VMAT2 protects against METH toxicity without enhancing the rewarding effects of the drug. Since the VMAT2-HI mice are protected from METH despite higher basal dopamine levels, this study suggests that METH toxicity depends more on the proper compartmentalization of synaptic dopamine than on the absolute amount of dopamine in the brain.

  • pacap38 increases vesicular Monoamine Transporter 2 vmat2 expression and attenuates methamphetamine toxicity
    Neuropeptides, 2008
    Co-Authors: Thomas S Guillot, Jason R Richardson, Minzheng Wang, Tonya N Taylor, Brian J Ciliax, O Zachrisson, A Mercer, Gary W Miller
    Abstract:

    Pituitary adenylyl cyclase activating polypeptide, 38 amino acids (PACAP38) is a brain-gut peptide with diverse physiological functions and is neuroprotective in several models of neurological disease. In this study, we show that systemic administration of PACAP38, which is transported across the blood-brain barrier, greatly reduces the neurotoxicity of methamphetamine (METH). Mice treated with PACAP38 exhibited an attenuation of striatal dopamine loss after METH exposure as well as greatly reduced markers of oxidative stress. PACAP38 treatment also prevented striatal neuroinflammation after METH administration as measured by overexpression of glial fibrillary acidic protein (GFAP), an indicator of astrogliosis, and glucose Transporter 5 (GLUT5), a marker of microgliosis. In PACAP38 treated mice, the observed protective effects were not due to an altered thermal response to METH. Since the mice were not challenged with METH until 28 days after PACAP38 treatment, this suggests the neuroprotective effects are mediated by regulation of gene expression. At the time of METH administration, PACAP38 treated animals exhibited a preferential increase in the expression and function of the vesicular Monoamine Transporter (VMAT2). Genetic reduction of VMAT2 has been shown to increase the neurotoxicity of METH, thus we propose that the increased expression of VMAT2 may underlie the protective actions of PACAP38 against METH. The ability of PACAP38 to increase VMAT2 expression suggests that PACAP38 signaling pathways may constitute a novel therapeutic approach to treat and prevent disorders of dopamine storage.

  • acute exposure to aroclor 1016 or 1260 differentially affects dopamine Transporter and vesicular Monoamine Transporter 2 levels
    Toxicology Letters, 2004
    Co-Authors: Jason R Richardson, Gary W Miller
    Abstract:

    Polychlorinated biphenyls (PCBs) have been shown to specifically target the dopaminergic nervous system, resulting in long-term reduction of striatal dopamine (DA) levels. However, the mechanism(s) by which PCBs exert this effect is not known. Here we report that decreased striatal dopamine levels are observed 1, 7, and 14 days after acute exposure to the common PCB mixtures Aroclor 1016 or 1260. Dopamine Transporter (DAT) levels were decreased at all time points in Aroclor 1016 treated animals, and on Days 1 and 7 in Aroclor 1260 treated animals. Vesicular Monoamine Transporter 2 (VMAT2) levels were not affected by Aroclor 1016, but were significantly decreased 14 days after exposure to Aroclor 1260. Tyrosine hydroxylase expression, a marker of dopamine neuron integrity, was not significantly affected by PCB exposure at any time. These data suggest that PCB-induced reductions in striatal dopamine may be mediated by alterations in DAT and VMAT2 expression.

  • increased mptp neurotoxicity in vesicular Monoamine Transporter 2 heterozygote knockout mice
    Journal of Neurochemistry, 2002
    Co-Authors: Raul R Gainetdinov, Fabio Fumagalli, Yanmin Wang, Sara R Jones, Allan I Levey, Gary W Miller
    Abstract:

    The neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been proposed to be attenuated by sequestration into intracellular vesicles by the vesicular Monoamine Transporter (VMAT2). The purpose of this study was to determine if mice with genetically reduced levels of VMAT2 (heterozygote knockout; VMAT2 +/-) were more vulnerable to MPTP. Striatal dopamine (DA) content, the levels of DA Transporter (DAT) protein, and the expression of glial fibrillary acidic protein (GFAP) mRNA, a marker of gliosis, were assessed as markers of MPTP neurotoxicity. In all parameters measured VMAT2 +/- mice were more sensitive than their wild-type littermates (VMAT2 +/+). Administration of MPTP (7.5, 15, or 30 mg/kg, b.i.d.) resulted in dose-dependent reductions in striatal DA levels in both VMAT2 +/- and VMAT2 +/+ animals, but the neurotoxic potency of MPTP was approximately doubled in the VMAT2 +/- mice: 59 versus 23% DA loss 7 days after 7.5 mg/kg dose for VMAT2 +/- and VMAT2 +/+ mice, respectively. Dopaminergic nerve terminal integrity, as assessed by DAT protein expression, also revealed more drastic reductions in the VMAT2 +/- mice: 59 versus 35% loss at 7.5 mg/kg and 95 versus 58% loss at 15 mg/kg for VMAT2 +/- and VMAT2 +/+ mice, respectively. Expression of GFAP mRNA 2 days after MPTP was higher in the VMAT2 +/- mice than in the wild-type: 15.8- versus 7.8-fold increase at 7.5 mg/kg and 20.1- versus 9.6-fold at 15 mg/kg for VMAT2 +/- and VMAT2 +/+ mice, respectively. These observations clearly demonstrate that VMAT2 +/- mice are more susceptible to the neurotoxic effects of MPTP, suggesting that VMAT2-mediated sequestration of the neurotoxin into vesicles may play an important role in attenuating MPTP toxicity in vivo.

S Stahl - One of the best experts on this subject based on the ideXlab platform.

Annette E Fleckenstein - One of the best experts on this subject based on the ideXlab platform.

  • psychostimulant induced alterations in vesicular Monoamine Transporter 2 function neurotoxic and therapeutic implications
    Neuropharmacology, 2009
    Co-Authors: Annette E Fleckenstein, Trent J Volz, Glen R Hanson
    Abstract:

    The vesicular Monoamine Transporter-2 (VMAT-2) is an important regulator of intraneuronal Monoamine concentrations and disposition as this protein sequesters critical cytoplasmic Monoaminergic transmitters and contributes to their subsequent exocytotic release. This review primarily discusses the impact of psychoactive drugs (including those with abuse potential) on dopamine (DA)-related VMAT-2 and its function. In particular, the different responses by DA-related VMAT-2 and associated vesicles to plasmalemmal uptake blockers like methylphenidate and releasers like methamphetamine are presented. Recent preclinical findings suggest that vesicular Transporter systems are highly regulatable, both by changes in localization as well as alterations in the kinetics of the VMAT-2 protein. The capacity for such shifts in VMAT-2 functions suggests the presence of physiological regulation that likely influences the activity of DA systems. In addition, these findings may contribute to our understanding of the pathogenesis of a variety of DA-related disorders such as substance abuse and Parkinson's disease and also suggest new therapeutic targets for treating such diseases.

  • age dependent differences in dopamine Transporter and vesicular Monoamine Transporter 2 function and their implications for methamphetamine neurotoxicity
    Synapse, 2008
    Co-Authors: Trent J Volz, Glen R Hanson, Sarah J Farnsworth, Shane D Rowley, Annette E Fleckenstein
    Abstract:

    The abuse of methamphetamine (METH) is a serious public health problem because METH can cause persistent dopaminergic deficits in the brains of both animal models and humans. Surprisingly, adolescent postnatal day (PND)40 rats are resistant to these METH-induced deficits, whereas young adult PND90 rats are not. Studies described in this report used rotating disk electrode voltammetry and western blotting techniques to investigate whether there are age-dependent differences in Monoamine Transporter function in PND38-42 and PND88-92 rats that could contribute to this phenomenon. The initial velocities of dopamine (DA) transport into, METH-induced DA efflux from, and DA Transporter (DAT) immunoreactivity in striatal suspensions are greater in PND38-42 rats than in PND88-92 rats. DA transport velocities into vesicles that cofractionate with synaptosomal membranes after osmotic lysis are also greater in PND38-42 rats. However, there is no difference in vesicular Monoamine Transporter-2 (VMAT-2) immunoreactivity between the two age groups in this fraction. This suggests that younger rats have a greater capacity to sequester cytoplasmic DA into membrane-associated vesicles due to kinetically upregulated VMAT-2 and also have increased levels of functionally active DAT. In the presence of METH, these may provide additional routes of cellular efflux for DA that is released from vesicles into the cytoplasm and thereby prevent cytoplasmic DA concentrations in younger rats from rising to neurotoxic levels after drug administration. These findings provide novel insight into the age-dependent physiological regulation of neuronal DA sequestration and may advance the treatment of disorders involving abnormal DA disposition including substance abuse and Parkinson's disease.

  • impact of psychostimulants on vesicular Monoamine Transporter function
    European Journal of Pharmacology, 2003
    Co-Authors: Annette E Fleckenstein, Glen R Hanson
    Abstract:

    The vesicular Monoamine Transporter-2 (VMAT-2) facilitates the sequestration of catecholamines and serotonin into synaptic vesicles, and is therefore an essential regulator of Monoaminergic neuronal function. VMAT-2 proteins may also play a role in neuroprotection, since these Transporters have the capacity to sequester neurotoxins within vesicles. Recent studies have demonstrated that psychostimulants, particularly dopamine "releasers" and "reuptake inhibitors", differentially alter VMAT-2 function. As described in this review, these studies not only provide insight into the pharmacological actions of stimulants, but also mechanisms underlying neurodegenerative disorders, including Parkinson's disease.

  • methylphenidate redistributes vesicular Monoamine Transporter 2 role of dopamine receptors
    The Journal of Neuroscience, 2002
    Co-Authors: Veronica Sandoval, Evan L Riddle, Glen R Hanson, Annette E Fleckenstein
    Abstract:

    It is well accepted that methylphenidate (MPD) inhibits dopamine (DA) Transporter function. In addition to this effect, this study demonstrates that MPD increases vesicular [3H]DA uptake and binding of the vesicular Monoamine Transporter-2 (VMAT-2) ligand dihydrotetrabenazine (DHTBZ) in a dose- and time-dependent manner in purified striatal vesicles prepared from treated rats. This change did not result from residual MPD introduced by the original in vivo treatment, because application of MPD in vitro (< or =1 miccrom) was without effect, and higher concentrations decreased vesicular [3H]DA uptake. In addition, MPD treatment increased and decreased VMAT-2 immunoreactivity in striatal vesicle subcellular and plasmalemmal membrane fractions, respectively. The MPD-induced increase in both VMAT-2 immunoreactivity and DHTBZ binding was attenuated by pretreatment in vivo with either the DA D(1) receptor antagonist SCH23390 or the DA D2 receptor antagonist eticlopride. Coadministration of these antagonists in vivo inhibited completely the MPD-induced increase in DHTBZ binding in the purified vesicular preparation. These observations suggest a role for DA in the MPD-induced redistribution of VMAT-2. The implications of this phenomenon will be discussed.

  • differential trafficking of the vesicular Monoamine Transporter 2 by methamphetamine and cocaine
    European Journal of Pharmacology, 2002
    Co-Authors: Evan L Riddle, Glen R Hanson, Matthew K Topham, John W Haycock, Annette E Fleckenstein
    Abstract:

    High-dose administration of cocaine or methamphetamine to rats acutely (≤24 h) alters vesicular dopamine transport. This study elucidates the nature of these changes. Results reveal a differential redistribution of the vesicular Monoamine Transporter-2 (VMAT-2) within striatal synaptic terminals after drug treatment. In particular, cocaine shifts VMAT-2 protein from a synaptosomal membrane fraction to a vesicle-enriched fraction, as assessed ex vivo in fractions prepared from treated rats. In contrast, methamphetamine treatment redistributes VMAT-2 from a vesicle-enriched fraction to a location that is not retained in a synaptosomal preparation. These data suggest that psychostimulants acutely and differentially affect VMAT-2 subcellular localization.

Falk W Lohoff - One of the best experts on this subject based on the ideXlab platform.

  • deletion of the vesicular Monoamine Transporter 1 vmat1 slc18a1 gene affects dopamine signaling
    Brain Research, 2019
    Co-Authors: Falk W Lohoff, Thomas N Ferraro, Gregory V Carr, Bethany R Brookshire, Irwin Lucki
    Abstract:

    The vesicular Monoamine Transporter is involved in presynaptic catecholamine storage and neurotransmission. Two isoforms of the Transporter exist, VMAT1 and VMAT2, and both are expressed in the brain, though VMAT2 expression is more robust and has been more widely studied. In this study we investigated the role of VMAT1 KO on markers of dopaminergic function and neurotransmission, and dopamine-related behaviors. Null-mutant VMAT1 mice were studied behaviorally using the tail suspension test, elevated zero maze and locomotor activity assessments. Tissue Monoamines were measured both ex vivo and by using in vivo microdialysis. Protein expression of tyrosine hydroxylase and D2 dopamine receptors was measured using western blot analysis. Results show that VMAT1 KO mice have decreased dopamine levels in the frontal cortex, increased postsynaptic D2 expression, and lower frontal cortex tyrosine hydroxylase expression compared to WT mice. VMAT1 KO mice also show an exaggerated behavioral locomotor response to acute amphetamine treatment. We conclude that dopaminergic signaling is robustly altered in the frontal cortex of VMAT1 null-mutant mice and suggest that VMAT1 may be relevant to the pathogenesis and/or treatment of psychiatric illnesses including schizophrenia and bipolar disease.

  • functional genetic variants in the vesicular Monoamine Transporter 1 modulate emotion processing
    Molecular Psychiatry, 2014
    Co-Authors: Falk W Lohoff, Jon Kar Zubieta, Thomas N Ferraro, Rachel Hodge, Sneha Narasimhan, Aleksandra H Nall, Brian J Mickey, Mary M Heitzeg, Scott A Langenecker, Ryan Bogdan
    Abstract:

    Emotional behavior is in part heritable and often disrupted in psychopathology. Identification of specific genetic variants that drive this heritability may provide important new insight into molecular and neurobiological mechanisms involved in emotionality. Our results demonstrate that the presynaptic vesicular Monoamine Transporter 1 (VMAT1) Thr136Ile (rs1390938) polymorphism is functional in vitro, with the Ile allele leading to increased Monoamine transport into presynaptic vesicles. Moreover, we show that the Thr136Ile variant predicts differential responses in emotional brain circuits consistent with its effects in vitro. Lastly, deep sequencing of bipolar disorder (BPD) patients and controls identified several rare novel VMAT1 variants. The variant Phe84Ser was only present in individuals with BPD and leads to marked increase Monoamine transport in vitro. Taken together, our data show that VMAT1 polymorphisms influence Monoamine signaling, the functional response of emotional brain circuits and risk for psychopathology.

  • association study of the vesicular Monoamine Transporter gene slc18a2 with tardive dyskinesia
    Journal of Psychiatric Research, 2013
    Co-Authors: Clement C Zai, Falk W Lohoff, Arun K Tiwari, Marina Mazzoco, Vincenzo De Luca, Daniel J Muller, Sajid A Shaikh, Natalie Freeman
    Abstract:

    Tardive dyskinesia (TD) is an involuntary movement disorder that can occur in up to 25% of patients receiving long-term first-generation antipsychotic treatment. Its etiology is unclear, but family studies suggest that genetic factors play an important role in contributing to risk for TD. The vesicular Monoamine Transporter 2 (VMAT2) is an interesting candidate for genetic studies of TD because it regulates the release of neurotransmitters implicated in TD, including dopamine, serotonin, and GABA. VMAT2 is also a target of tetrabenazine, a drug used in the treatment of hyperkinetic movement disorders, including TD. We examined nine single-nucleotide polymorphisms (SNPs) in the SLC18A2 gene that encodes VMAT2 for association with TD in our sample of chronic schizophrenia patients (n = 217). We found a number of SNPs to be nominally associated with TD occurrence and the Abnormal Involuntary Movement Scale (AIMS), including the rs2015586 marker which was previously found associated with TD in the CATIE sample (Tsai et al., 2010), as well as the rs363224 marker, with the low-expression AA genotype appearing to be protective against TD (p = 0.005). We further found the rs363224 marker to interact with the putative functional D2 receptor rs6277 (C957T) polymorphism (p = 0.001), supporting the dopamine hypothesis of TD. Pending further replication, VMAT2 may be considered a therapeutic target for the treatment and/or prevention of TD.

  • association between polymorphisms in the vesicular Monoamine Transporter 1 gene vmat1 slc18a1 on chromosome 8p and schizophrenia
    Neuropsychobiology, 2008
    Co-Authors: Falk W Lohoff, Andrew E Weller, Paul J Bloch, Russell J Buono, Glenn A Doyle, Thomas N Ferraro, Wade H Berrettini
    Abstract:

    Linkage studies have suggested a susceptibility locus for schizophrenia (SZ) exists on chromosome 8p21–22. The vesicular Monoamine Transporter 1 gene (VMAT1), also known as SLC18A1, maps to this SZ su