Heinrich J G Matthies

Heinrich J G Matthies
University of Alabama at Birmingham | UAB · Department of Surgery

PhD

About

68
Publications
12,614
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Introduction
Heinrich J G Matthies currently works at the Department of Surgery, University of Alabama at Birmingham. Heinrich does research in Cell Biology, Genetics and Neuroscience. Their current project is 'Amphetamine actions and lipid interactions.' and dopamine and autism.
Additional affiliations
November 2017 - present
University of Alabama at Birmingham
Position
  • Professor (Assistant)
May 2011 - present
Vanderbilt University
Position
  • Research Assistant
January 2003 - December 2011
Vanderbilt University
Position
  • Research fellow, Research Instructor
Education
September 1987 - December 1992
University of Chicago
Field of study
  • Biology and Cell Physiology

Publications

Publications (68)
Article
Full-text available
Amphetamine (AMPH) is a psychostimulant that is commonly abused. The stimulant properties of AMPH are associated with its ability to increase dopamine (DA) neurotransmission. This increase is promoted by nonvesicular DA release mediated by reversal of DA transporter (DAT) function. Syntaxin 1 (Stx1) is a SNARE protein that is phosphorylated at Ser1...
Preprint
Full-text available
Amphetamine (AMPH), a psychostimulant commonly prescribed for the treatment of neuropsychiatric and neurological disorders, has a high liability for abuse. The abuse and psychomotor stimulant properties of AMPH are primarily associated with its ability to increase dopamine (DA) neurotransmission. This increase is mediated, in large part, by non-ves...
Article
Full-text available
Dysfunctional dopaminergic neurotransmission is central to movement disorders and mental diseases. The dopamine transporter (DAT) regulates extracellular dopamine levels but the genetic and mechanistic link between DAT function and dopamine-related pathologies is not clear. Particularly, the pathophysiological significance of monoallelic missense m...
Article
Full-text available
Reward modulates the saliency of a specific drug exposure and is essential for the transition to addiction. Numerous human PET–fMRI studies establish a link between midbrain dopamine (DA) release, DA transporter (DAT) availability, and reward responses. However, how and whether DAT function and regulation directly participate in reward processes re...
Article
Full-text available
Background: Altered dopamine (DA) signaling has been associated with autism spectrum disorder (ASD), a neurodevelopmental condition estimated to impact 1 in 54 children in the United States. There is growing evidence for alterations in both gastrointestinal function and oral microbiome composition in ASD. Recent work suggests that rare variants of...
Preprint
Full-text available
Parkinson's disease (PD) is a neurodegenerative disorder affecting over 6.1 million people worldwide. Studies of highly-penetrant mutations identified in early-onset familial parkinsonism have contributed to our understanding of the mechanisms underlying PD. Dopamine (DA) transporter (DAT) deficiency syndrome (DTDS) is a type of infantile parkinson...
Article
Full-text available
The precise regulation of synaptic dopamine (DA) content by the dopamine transporter (DAT) ensures the phasic nature of the DA signal, which underlies the ability of DA to encode reward prediction error, thereby driving motivation, attention, and behavioral learning. Disruptions to the DA system are implicated in a number of neuropsychiatric disord...
Article
Full-text available
The human dopamine (DA) transporter (hDAT) mediates clearance of DA. Genetic variants in hDAT have been associated with DA dysfunction, a complication associated with several brain disorders, including autism spectrum disorder (ASD). Here, we investigated the structural and behavioral bases of an ASD-associated in-frame deletion in hDAT at N336 (∆N...
Article
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Synthetic cathinones are similar in chemical structure to amphetamines, and their behavioral effects are associated with enhanced dopaminergic signaling. The past ten years of research on the common constituent of bath salts, MDPV (the synthetic cathinone 3,4-methylenedioxypyrovalerone), has aided the understanding of how synthetic cathinones act a...
Article
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Our laboratory recently characterized a novel autism spectrum disorder (ASD)-associated de novo missense mutation in the human dopamine transporter (hDAT) gene SLC6A3 (hDAT T356M). This hDAT variant exhibits dysfunctional forward and reverse transport properties that may contribute to DA dysfunction in ASD. Here, we report that Zn(2+) reverses, at...
Article
It has been shown that vitamin C (VC) is transported at synaptic boutons, but how this occurs has not been elucidated. This study investigates the role of the sodium-dependent vitamin C transporter-2 (SVCT2) in transporting VC at the cortical nerve terminal. Immunostaining of cultured mouse superior cervical ganglion cells showed the SVCT2 to be ex...
Article
Full-text available
Disrupted neuronal protein kinase B (Akt) signaling has been associated with dopamine (DA)-related neuropsychiatric disorders, including schizophrenia, a devastating mental illness. We hypothesize that proper DA neurotransmission is therefore dependent upon intact neuronal Akt function. Akt is activated by phosphorylation of two key residues: Thr30...
Article
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Hypersecretion of norepinephrine (NE) and angiotensin II (AngII) is a hallmark of major prevalent cardiovascular diseases that contribute to cardiac pathophysiology and morbidity. Herein, we explore whether heterodimerization of presynaptic AngII AT1 receptor (AT1-R) and NE α2C-adrenergic receptor (α2C-AR) could underlie their functional cross-talk...
Article
Full-text available
Syntaxin 1 (STX1) is a presynaptic plasma membrane protein that coordinates synaptic vesicle fusion. STX1 also regulates the function of neurotransmitter transporters, including the dopamine (DA) transporter (DAT). The DAT is a membrane protein that controls DA homeostasis through the high-affinity re-uptake of synaptically released DA. We adopt ne...
Article
Full-text available
Emerging evidence associates dysfunction in the dopamine (DA) transporter (DAT) with the pathophysiology of autism spectrum disorder (ASD). The human DAT (hDAT; SLC6A3) rare variant with an Ala to Val substitution at amino acid 559 (hDAT A559V) was previously reported in individuals with bipolar disorder or attention-deficit hyperactivity disorder...
Article
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Phosphatidylinositol (4,5)-bisphosphate (PIP2) regulates the function of ion channels and transporters. Here, we demonstrate that PIP2 directly binds the human dopamine (DA) transporter (hDAT), a key regulator of DA homeostasis and a target of the psychostimulant amphetamine (AMPH). This binding occurs through electrostatic interactions with positi...
Article
Full-text available
De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT)...
Article
Full-text available
The serotonergic system regulates a wide range of behavior, including mood and impulsivity, and its dysregulation has been associated with mood disorders, autism spectrum disorder, and addiction. Diabetes is a risk factor for these conditions. Insulin resistance in the brain is specifically associated with susceptibility to psychostimulant abuse. H...
Article
Full-text available
De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT)...
Article
Full-text available
Nerve functions require phosphatidylinositol-4,5-bisphosphate (PIP2) that binds to ion channels, thereby controlling their gating. Channel properties are also attributed to serotonin transporters (SERTs); however, SERT regulation by PIP2 has not been reported. SERTs control neurotransmission by removing serotonin from the extracellular space. An in...
Article
Full-text available
Neuropsychopharmacology, the official publication of the American College of Neuropsychopharmacology, publishing the highest quality original research and advancing our understanding of the brain and behavior.
Chapter
Neurotransmitters are chemical messengers by which neurons communicate with each other. High affinity uptake of neurotransmitters is mediated by transporter proteins and is the most common mechanism for the termination of neurotransmitter signaling. Transporters clear neurotransmitters not only to control the timing of neurochemical communication,...
Article
Full-text available
The alpha2 adrenergic receptor (α(2)-AR) antagonist yohimbine is a widely used tool for the study of anxiogenesis and stress-induced drug-seeking behavior. We previously demonstrated that yohimbine paradoxically depresses excitatory transmission in the bed nucleus of the stria terminalis (BNST), a region critical to the integration of stress and re...
Data
HF feeding results in weight gain as well as increased caloric intake and plasma insulin, but not changes in plasma glucose. The HF-fed rats showed a (A) significant increase in total caloric intake (n = 13/group; *p<0.05 by Student's t-test) and (B) weight gain (n = 13/group; *p<0.05 by Student's t-test) over the 28-day feeding period. On day 28,...
Article
Full-text available
Background: The prevalence of obesity has increased dramatically worldwide. The obesity epidemic begs for novel concepts and therapeutic targets that cohesively address "food-abuse" disorders. We demonstrate a molecular link between impairment of a central kinase (Akt) involved in insulin signaling induced by exposure to a high-fat (HF) diet and d...
Data
Mutations in γtub37C cause spindle and chromosome defects in most, but not all, prometaphase I oocytes. Fixed oocytes were treated with antibodies against α-tubulin and histone H3 phosphorylated at serine 10 (phH3S10), as well as the DNA dye DAPI. Arrowheads point to aberrant phH3S10-positive threads projecting from the chromosome mass. (A) A γtub3...
Data
The phH3S10 antibody robustly localizes to DNA threads connecting achiasmate chromosomes. Fixed FM7w/yw; pol oocytes were treated with antibodies against α-tubulin and histone H3 phosphorylated at serine 10 (phH3S10), as well as the DNA dye DAPI. Heterozygosity for the balancer chromosome FM7w results in oocytes with achiasmate Xs, as well as achia...
Data
Defects in spindle morphology, spindle position, and chromosome alignment are observed in a living γtub37CP162L mutant oocyte. Stills from Video S3 are shown in Figure 4. OliGreen (yellow) labels the DNA and rhodamine-conjugated tubulin (blue) labels the spindle. The video is a projection from Z stack. (MOV)
Data
γTub37C protein is expressed in γtub37CP162L mutant ovaries. Shown is a Western blot using the DrosC anti-γTub37C antibody recognizing the C-terminus of γTub37C. Each lane represents lysate from 50 ovaries. Lanes 1 and 2 were loaded with 1 and 2 µl, respectively, of lysate from wild-type ovaries. Lanes 3 and 4 were loaded with 1 and 2 µl, respectiv...
Data
The spindle loses and regains bipolarity after nuclear envelope breakdown in a living γtub37CP162L mutant oocyte. OliGreen (yellow) labels the DNA and rhodamine-conjugated tubulin (blue) labels the spindle. The video is a projection from Z stack. (MOV)
Data
The spindle and chromosomes remain relatively stable for long periods in a wild-type oocyte. OliGreen (yellow) labels the DNA and rhodamine-conjugated tubulin (blue) labels the spindle. The video is a projection from Z stack. (MOV)
Data
The spindle and microtubules move rapidly resulting in the dissolution of the spindle in a living γtub37CP162L mutant oocyte. OliGreen (yellow) labels the DNA and rhodamine-conjugated tubulin (blue) labels the spindle. Videos are projections from Z stack. (MOV)
Data
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Orientation of CID foci. (PDF)
Data
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Position of the oocyte nucleus within the oocyte. (PDF)
Article
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In many animal species the meiosis I spindle in oocytes is anastral and lacks centrosomes. Previous studies of Drosophila oocytes failed to detect the native form of the germline-specific γ-tubulin (γTub37C) in meiosis I spindles, and genetic studies have yielded conflicting data regarding the role of γTub37C in the formation of bipolar spindles at...
Article
Full-text available
Plasmalemmal neurotransmitter transporters (NTTs) regulate the level of neurotransmitters, such as dopamine (DA) and glutamate, after their release at brain synapses. Stimuli including protein kinase C (PKC) activation can lead to the internalization of some NTTs and a reduction in neurotransmitter clearance capacity. We found that the protein Flot...
Article
Full-text available
Noradrenergic signaling in the CNS plays an essential role in circuits involving attention, mood, memory, and stress as well as providing pivotal support for autonomic function in the peripheral nervous system. The high-affinity norepinephrine (NE) transporter (NET) is the primary mechanism by which noradrenergic synaptic transmission is terminated...
Article
Dopamine (DA) is a neurotransmitter implicated in multiple functions, including movement, cognition, motivation, and reward. The DA transporter (DAT) is responsible for clearing extracellular DA, thereby terminating DA neurotransmission. Previously, it has been shown that insulin signaling through protein kinase B/Akt regulates DAT function by fine...
Article
Full-text available
The norepinephrine transporter (NET) is a presynaptic plasma membrane protein that mediates reuptake of synaptically released norepinephrine. NET is also a major target for medications used for the treatment of depression, attention deficit/hyperactivity disorder, narcolepsy, and obesity. NET is regulated by numerous mechanisms, including catalytic...
Article
Full-text available
The neurotransmitter dopamine (DA) modulates brain circuits involved in attention, reward, and motor activity. Synaptic DA homeostasis is primarily controlled via two presynaptic regulatory mechanisms, DA D(2) receptor (D(2)R)-mediated inhibition of DA synthesis and release, and DA transporter (DAT)-mediated DA clearance. D(2)Rs can physically asso...
Article
Full-text available
The Na(+)/Cl(-)-dependent serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) is a critical element in neuronal 5-HT signaling, being responsible for the efficient elimination of 5-HT after release. SERTs are not only targets for exogenous addictive and therapeutic agents but also can be modulated by endogenous, receptor-linked signaling pathw...
Data
PKGI antibody specifically labels RN46A cells. The data provided demonstrate the specificity of the PKG antibody. Additional Figure 1. PKGI antibody specifically labels RN46A cells. RN46A cells were fixed, permeabilized, stained, and imaged by confocal microscopy as described in Methods. Left panel) RN46A cells stained with anti-PKGI (Assay Designs...
Data
siRNA knockdown of PKGI due to low transfection efficiency. The data provided support the results shown in Figure 4 by demonstrating analysis of the siRNA-mediated protein knockdown and corresponding transfection efficiency. Additional Figure 2. siRNA knockdown of PKGI due to low transfection efficiency. HeLa cells were plated identically to those...
Article
Full-text available
Reuptake of synaptic norepinephrine (NE) via the antidepressant-sensitive NE transporter (NET) supports efficient noradrenergic signaling and presynaptic NE homeostasis. Limited, and somewhat contradictory, information currently describes the axonal transport and localization of NET in neurons. We elucidate NET localization in brain and superior ce...
Article
Full-text available
Amphetamine (AMPH) and its derivatives are regularly used in the treatment of a wide array of disorders such as attention-deficit hyperactivity disorder (ADHD), obesity, traumatic brain injury, and narcolepsy (Prog Neurobiol 75:406-433, 2005; J Am Med Assoc 105:2051-2054, 1935; J Am Acad Child Adolesc Psychiatry 41:514-521, 2002; Neuron 43:261-269,...
Article
A continuous supply of fusion-competent synaptic vesicles is essential for sustainable neurotransmission. Drosophila mutations of the dicistronic stoned locus disrupt normal vesicle cycling and cause functional deficits in synaptic transmission. Although both Stoned A and B proteins putatively participate in reconstituting synaptic vesicles, their...
Article
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Nod, a nonmotile kinesin-like protein, plays a critical role in segregating achiasmate chromosomes during female meiosis. In addition to localizing to oocyte chromosomes, we show that functional full-length Nod-GFP (Nod(FL)-GFP) localizes to the posterior pole of the oocyte at stages 9-10A, as does kinesin heavy chain (KHC), a plus end-directed mot...
Article
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The rolling blackout (rbo) gene encodes an integral plasma membrane lipase required for Drosophila phototransduction. Photoreceptors are enriched for the RBO protein, and temperature-sensitive rbo mutants show reversible elimination of phototransduction within minutes, demonstrating an acute requirement for the protein. The block is activity depend...
Article
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A screen for Drosophila synaptic dysfunction mutants identified slug-a-bed (slab). The slab gene encodes ceramidase, a central enzyme in sphingolipid metabolism and regulation. Sphingolipids are major constituents of lipid rafts, membrane domains with roles in vesicle trafficking, and signaling pathways. Null slab mutants arrest as fully developed...
Article
Macroorchidism (i.e., enlarged testicles) and mental retardation are the two hallmark symptoms of Fragile X syndrome (FraX). The disease is caused by loss of fragile X mental retardation protein (FMRP), an RNA-binding translational regulator. We previously established a FraX model in Drosophila, showing that the fly FMRP homologue, dFXR, acts as a...
Article
This chapter presents the various techniques used to move from mutant to gene to gene product function by using Drosophila as a genetic model system for cellular neurobiology. It also outlines the various resources and experimental approaches available to the Drosophila neurobiologist. Selected methods of particular interest are discussed in detail...
Article
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Calcium/calmodulin dependent kinase II (CaMKII), PDZ-domain scaffolding protein Discs-large (DLG), immunoglobin superfamily cell adhesion molecule Fasciclin 2 (FAS2) and the position specific (PS) integrin receptors, including betaPS and its alpha partners (alphaPS1, alphaPS2, alphaPS3/alphaVolado), are all known to regulate the postembryonic devel...
Article
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NOD is a Drosophila chromosome-associated kinesin-like protein that does not fall into the chromokinesin subfamily. Although NOD lacks residues known to be critical for kinesin function, we show that microtubules activate the ATPase activity of NOD >2000-fold. Biochemical and genetic analysis of two genetically identified mutations of NOD (NOD(DTW)...
Article
Fragile X mental retardation gene (FMR1) encodes an RNA binding protein that acts as a negative translational regulator. We have developed a Drosophila fragile X syndrome model using loss-of-function mutants and overexpression of the FMR1 homolog (dfxr). dfxr nulls display enlarged synaptic terminals, whereas neuronal overexpression results in fewe...
Article
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Drosophila melanogaster oocytes heterozygous for mutations in the alpha-tubulin 67C gene (alphatub67C) display defects in centromere positioning during prometaphase of meiosis I. The centromeres do not migrate to the poleward edges of the chromatin mass, and the chromatin fails to stretch during spindle lengthening. These results suggest that the p...
Article
Full-text available
The segregation of homologous chromosomes from one another is the essence of meiosis. In many organisms, accurate segregation is ensured by the formation of chiasmata resulting from crossing over. Drosophila melanogaster females use this type of recombination-based system, but they also have mechanisms for segregating achiasmate chromosomes with hi...
Article
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Previous genetic and biochemical studies have led to the hypothesis that the essential mitotic bipolar kinesin, KLP61F, cross-links and slides microtubules (MTs) during spindle assembly and function. Here, we have tested this hypothesis by immunofluorescence and immunoelectron microscopy (immunoEM). We show that Drosophila embryonic spindles at met...
Article
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We have used time-lapse laser scanning confocal microscopy to directly examine microtubule reorganization during meiotic spindle assembly in living Drosophila oocytes. These studies indicate that the bipolarity of the meiosis I spindle is not the result of a duplication and separation of centrosomal microtubule organizing centers (MTOCs). Instead,...
Article
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We have used time-lapse laser scanning con-focal microscopy to directly examine microtubule reorganization during meiotic spindle assembly in living Drosophila oocytes. These studies indicate that the bi-polarity of the meiosis I spindle is not the result of a duplication and separation of centrosomal microtubule organizing centers (MTOCs). Instead...
Article
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Kinesin is an ubiquitous heterotetrameric microtubule-based motor which translocates membrane-bound organelles. Since organelle motility and motor protein function can be regulated by components of signaling pathways, the ability of purified bovine brain kinesin (kinesin) to be phosphorylated and to recognize calmodulin (CaM) was tested. Extensivel...
Article
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Dorsal root ganglion (DRG) neurons cultured from neonatal rats contained high concentrations of protein kinase C (PKC). Normally, the majority of the enzyme activity was found in the cytosol and considerably less was associated with the membrane fraction. Upon incubation with the phorbol ester phorbol dibutyrate (PDBu, 10(-6) M) for 20 min, PKC act...
Article
Full-text available
Dorsal root ganglion (DRG) neurons cultured from neonatal rats contained high concentrations of protein kinase C (PKC). Normally, the majority of the enzyme activity was found in the cytosol and considerably less was associated with the membrane fraction. Upon incubation with the phorbol ester phorbol dibutyrate (PDBu, 10(-6) M) for 20 min, PKC act...
Article
Catecholamine secretion from PC-12 cells can be triggered by agents that increase intracellular Ca2+ and is enhanced by phorbol esters and agents that elevate intracellular cAMP concentrations. In mutant PC-12 cells lacking cAMP-dependent protein kinase (PK-A) in which protein kinase C (PK-C) was down-regulated, Ca2+-dependent secretion occurred no...
Chapter
It is well established that Ca2+ acts as an essential second messenger in virtually all cell types (Berridge and Irvine, 1984). Thus, regulation of the concentration of cytoplasmic free Ca2+, [Ca2+]i is of great importance in the regulation of cell function. One way in which [Ca2+]i can be readily increased is by opening specific voltage-sensitive...
Article
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We investigated the effects of phorbol esters on protein kinase C (PKC) activity and on neurotransmitter release from cultured neuronal cells. Both differentiated and undifferentiated PC12 pheochromocytoma cells contained high levels of protein PKC. Under normal conditions all the enzyme activity was found in the cytoplasm. Addition of the phorbol...
Article
Full-text available
We have followed the transfer of newly synthesized cholesterol to the plasma membrane in cultured fibroblasts using cholesterol oxidase as a probe. Since the enzyme has access only to the plasma membrane in intact cells, it permits the discrimination of cell surface and endogenous cholesterol. Cholesterol synthesized from radiolabeled acetate was t...
Article
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We have used the highly variable and conditional susceptibility of cholesterol oxidase to probe molecular rearrangements in the human red cell membrane. Cholesterol in the intact erythrocyte normally is not a substrate for this enzyme. Susceptibility was induced however, by these pretreatments: mild enrichment in membrane cholesterol, exposure to g...

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