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Articles 31 - 60 of 95

Full-Text Articles in Pharmacy and Pharmaceutical Sciences

Glutamate Transporter Control Of Ambient Glutamate Levels, Weinan Sun, Denis M. Shchepakin, Leonid Kalachev, Michael P. Kavanaugh Apr 2014

Glutamate Transporter Control Of Ambient Glutamate Levels, Weinan Sun, Denis M. Shchepakin, Leonid Kalachev, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Accurate knowledge of the ambient extracellular glutamate concentration in brain is required for understanding its potential impacts on tonic and phasic receptor signaling. Estimates of ambient glutamate based on microdialysis measurements are generally in the range of ∼2–10 μM, approximately 100-fold higher than estimates based on electrophysiological measurements of tonic NMDA receptor activity (∼25–90 nM). The latter estimates are closer to the low nanomolar estimated thermodynamic limit of glutamate transporters. The reasons for this discrepancy are not known, but it has been suggested that microdialysis measurements could overestimate ambient extracellular glutamate because of reduced glutamate transporter activity in a …

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Hilar Mossy Cells Provide The First Glutamatergic Synapses To Adult-Born Dentate Granule Cells, Jessica H. Chancey, David J. Poulsen, Jacques I. Wadiche, Linda Overstreet-Wadiche Feb 2014

Hilar Mossy Cells Provide The First Glutamatergic Synapses To Adult-Born Dentate Granule Cells, Jessica H. Chancey, David J. Poulsen, Jacques I. Wadiche, Linda Overstreet-Wadiche

Biomedical and Pharmaceutical Sciences Faculty Publications

Adult-generated granule cells (GCs) in the dentate gyrus must establish synapses with preexisting neurons to participate in network activity. To determine the source of early glutamatergic synapses on newborn GCs in adult mice, we examined synaptic currents at the developmental stage when NMDA receptor-mediated silent synapses are first established. We show that hilar mossy cells provide initial glutamatergic synapses as well as disynaptic GABAergic input to adult-generated dentate GCs.

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Phenoxybenzamine Is Neuroprotective In A Rat Model Of Severe Traumatic Brain Injury, Thomas Rau, Aakriti Kothiwal, Annela Rova, Joseph F. Rhoderick, David J. Poulsen Jan 2014

Phenoxybenzamine Is Neuroprotective In A Rat Model Of Severe Traumatic Brain Injury, Thomas Rau, Aakriti Kothiwal, Annela Rova, Joseph F. Rhoderick, David J. Poulsen

Biomedical and Pharmaceutical Sciences Faculty Publications

Phenoxybenzamine (PBZ) is an FDA approved α-1 adrenergic receptor antagonist that is currently used to treat symptoms of pheochromocytoma. However, it has not been studied as a neuroprotective agent for traumatic brain injury (TBI). While screening neuroprotective candidates, we found that phenoxybenzamine reduced neuronal death in rat hippocampal slice cultures following exposure to oxygen glucose deprivation (OGD). Using this system, we found that phenoxybenzamine reduced neuronal death over a broad dose range (0.1 μM–1 mM) and provided efficacy when delivered up to 16 h post-OGD. We further tested phenoxybenzamine in the rat lateral fluid percussion model of TBI. When administered …

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Analgesic Effect Of A Mixed T-Type Channel Inhibitor/Cb2 Receptor Agonist, Vinicius M. Gadotti, Haitao You, Ravil R. Petrov, N. Daniel Berger, Philippe Diaz, Gerald W. Zamponi Jul 2013

Analgesic Effect Of A Mixed T-Type Channel Inhibitor/Cb2 Receptor Agonist, Vinicius M. Gadotti, Haitao You, Ravil R. Petrov, N. Daniel Berger, Philippe Diaz, Gerald W. Zamponi

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Cannabinoid receptors and T-type calcium channels are potential targets for treating pain. Here we report on the design, synthesis and analgesic properties of a new mixed cannabinoid/T-type channel ligand, NMP-181. Results: NMP-181 action on CB1 and CB2 receptors was characterized in radioligand binding and in vitro GTP gamma[S-35] functional assays, and block of transiently expressed human Cav3.2 T-type channels by NMP-181 was analyzed by patch clamp. The analgesic effects and in vivo mechanism of action of NMP-181 delivered spinally or systemically were analyzed in formalin and CFA mouse models of pain. NMP-181 inhibited peak Ca(V)3.2 currents with IC50 values …

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Mri Of Neuronal Recovery After Low-Dose Methamphetamine Treatment Of Traumatic Brain Injury In Rats, Guang Liang Ding, Michael Chopp, David J. Poulsen, Lian Li, Changsheng Qu, Qingjiang Li, Siamak P. Nejad-Davarani, John S. Budaj, Hongtao Wu, Asim Mahmood, Quan Jiang Apr 2013

Mri Of Neuronal Recovery After Low-Dose Methamphetamine Treatment Of Traumatic Brain Injury In Rats, Guang Liang Ding, Michael Chopp, David J. Poulsen, Lian Li, Changsheng Qu, Qingjiang Li, Siamak P. Nejad-Davarani, John S. Budaj, Hongtao Wu, Asim Mahmood, Quan Jiang

Biomedical and Pharmaceutical Sciences Faculty Publications

We assessed the effects of low dose methamphetamine treatment of traumatic brain injury (TBI) in rats by employing MRI, immunohistology, and neurological functional tests. Young male Wistar rats were subjected to TBI using the controlled cortical impact model. The treated rats (n = 10) received an intravenous (iv) bolus dose of 0.42 mg/kg of methamphetamine at eight hours after the TBI followed by continuous iv infusion for 24 hrs. The control rats (n = 10) received the same volume of saline using the same protocol. MRI scans, including T2-weighted imaging (T2WI) and diffusion tensor imaging (DTI), were performed one day …

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Early Alzheimer's And Parkinson's Disease Pathology In Urban Children: Friend Versus Foe Responses—It Is Time To Face The Evidence, Lilian Calderón-Garcidueñas, Maricela Franco-Lira, Antonieta Mora-Tiscareño, Humberto Medina-Cortina, Ricardo Torres-Jardon, Michael Kavanaugh Jan 2013

Early Alzheimer's And Parkinson's Disease Pathology In Urban Children: Friend Versus Foe Responses—It Is Time To Face The Evidence, Lilian Calderón-Garcidueñas, Maricela Franco-Lira, Antonieta Mora-Tiscareño, Humberto Medina-Cortina, Ricardo Torres-Jardon, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Chronic exposure to particulate matter air pollution is known to cause inflammation leading to respiratory- and cardiovascularrelated sickness and death. Mexico City Metropolitan Area children exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, and innate and adaptive immune responses. Early dysregulated neuroinflammation, brain microvascular damage, production of potent vasoconstrictors, and perturbations in the integrity of the neurovascular unit likely contribute to progressive neurodegenerative processes. The accumulation of misfolded proteins coincides with the anatomical distribution observed in the early stages of both Alzheimer's and Parkinson's diseases. We contend misfolding of hyperphosphorylated tau (HPrc), alpha-synuclein, and beta-amyloid could …

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Exposure To Urban Air Pollution And Bone Health In Clinically Healthy Six-Year-Old Children, Lilian Calderón-Garcidueñas, Antonieta Mora-Tiscareño, Maricela Franco-Lira, Ricardo Torres-Jardon, Bernardo Pena-Cruz, Carolina Palacios-López, Hongtu Zhu, Linglong Kong, Nicolas Mendoza-Mendoza, Hortencia Montesinoscorrea, Lina Romero, Gildardo Valencia-Salazar, Michael Kavanaugh, Silvestre Frenk Jan 2013

Exposure To Urban Air Pollution And Bone Health In Clinically Healthy Six-Year-Old Children, Lilian Calderón-Garcidueñas, Antonieta Mora-Tiscareño, Maricela Franco-Lira, Ricardo Torres-Jardon, Bernardo Pena-Cruz, Carolina Palacios-López, Hongtu Zhu, Linglong Kong, Nicolas Mendoza-Mendoza, Hortencia Montesinoscorrea, Lina Romero, Gildardo Valencia-Salazar, Michael Kavanaugh, Silvestre Frenk

Biomedical and Pharmaceutical Sciences Faculty Publications

Air pollution induces systemic inflammation, as well as respiratory, myocardial and brain inflammation in children. Peak bone mass is influenced by environmental factors. We tested the hypothesis that six-year-olds with lifetime exposures to urban air pollution will have alterations in inflammatory markers and bone mineral density (BMD) as opposed to low-polluted city residents when matched for BMI, breast feeding history, skin phototype, age, sex and socioeconomic status. This pilot study included 20 children from Mexico City (MC) (6.17 years ± 0.63 years) and 15 controls (6.27 years ± 0.76 years). We performed full paediatric examinations, a history of outdoor exposures, …

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Novel Dicarboxylate Selectivity In An Insect Glutamate Transporter Homolog, Hui Wang, Avi M. Rascoe, David Charles Holley, Eric Gouaux, Michael Kavanaugh Jan 2013

Novel Dicarboxylate Selectivity In An Insect Glutamate Transporter Homolog, Hui Wang, Avi M. Rascoe, David Charles Holley, Eric Gouaux, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Mammals express seven transporters from the SLC1 (solute carrier 1) gene family, including five acidic amino acid transporters (EAAT1-5) and two neutral amino acid transporters (ASCT1-2). In contrast, insects of the order Diptera possess only two SLC1 genes. In this work we show that in the mosquito Culex quinquefasciatus, a carrier of West Nile virus, one of its two SLC1 EAAT-like genes encodes a transporter that displays an unusual selectivity for dicarboxylic acids over acidic amino acids. In eukaryotes, dicarboxylic acid uptake has been previously thought to be mediated exclusively by transporters outside the SLC1 family. The dicarboxylate selectivity was …

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Brain Immune Interactions And Air Pollution: Macrophage Inhibitory Factor (Mif), Prion Cellular Protein (Prpc), Interleukin-6 (Il-6), Interleukin 1 Receptor Antagonist (Il-1ra), And Interleukin-2 (Il-2) In Cerebrospinal Fluid And Mif In Serum Differentiate Urban Children Exposed To Severe Vs. Low Air Pollution, Lilian Calderón-Garcidueñas, Janet V. Cross, Maricela Franco-Lira, Mariana Aragón-Flores, Michael Kavanaugh, Ricardo Torres-Jardon, Chih-Kai Chao, Charles Thompson, Jing Chang, Hongtu Zhu, Amedeo D'Angiulli Jan 2013

Brain Immune Interactions And Air Pollution: Macrophage Inhibitory Factor (Mif), Prion Cellular Protein (Prpc), Interleukin-6 (Il-6), Interleukin 1 Receptor Antagonist (Il-1ra), And Interleukin-2 (Il-2) In Cerebrospinal Fluid And Mif In Serum Differentiate Urban Children Exposed To Severe Vs. Low Air Pollution, Lilian Calderón-Garcidueñas, Janet V. Cross, Maricela Franco-Lira, Mariana Aragón-Flores, Michael Kavanaugh, Ricardo Torres-Jardon, Chih-Kai Chao, Charles Thompson, Jing Chang, Hongtu Zhu, Amedeo D'Angiulli

Biomedical and Pharmaceutical Sciences Faculty Publications

Mexico City Metropolitan Area children chronically exposed to high concentrations of air pollutants exhibit an early brain imbalance in genes involved in oxidative stress, inflammation, innate and adaptive immune responses along with accumulation of misfolded proteins observed in the early stages of Alzheimer and Parkinson's diseases. A complex modulation of serum cytokines and chemokines influences children's brain structural and gray/white matter volumetric responses to air pollution. The search for biomarkers associating systemic and CNS inflammation to brain growth and cognitive deficits in the short term and neurodegeneration in the long-term is our principal aim. We explored and compared a profile …

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Oxygen Glucose Deprivation In Rat Hippocampal Slice Cultures Results In Alterations In Carnitine Homeostasis And Mitochondrial Dysfunction, Thomas Rau, Qing Lu, Shruti Sharma, Xutong Sun, Gregory Leary, Matthew L. Beckman, Yal Hou, Mark S. Wainwright, Michael P. Kavanaugh, David J. Poulsen, Stephen M. Black Sep 2012

Oxygen Glucose Deprivation In Rat Hippocampal Slice Cultures Results In Alterations In Carnitine Homeostasis And Mitochondrial Dysfunction, Thomas Rau, Qing Lu, Shruti Sharma, Xutong Sun, Gregory Leary, Matthew L. Beckman, Yal Hou, Mark S. Wainwright, Michael P. Kavanaugh, David J. Poulsen, Stephen M. Black

Biomedical and Pharmaceutical Sciences Faculty Publications

Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR) supplementation. Utilizing neonatal rat hippocampal slice cultures we …

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Identifying Neurotransmitter Spill-Over In Hippocampal Field Recordings, Emily Stone, Katie Hoffman, Michael P. Kavanaugh Aug 2012

Identifying Neurotransmitter Spill-Over In Hippocampal Field Recordings, Emily Stone, Katie Hoffman, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

A model of synaptic and extra-synaptic excitatory signaling in the hippocampus is presented. The model is used to analytically evaluate the potential contributions of homosynaptic and heterosynaptic glutamate spill-over to receptor signaling during an electrophysiological experiment in which glutamate transporters are pharmacologically blocked. Inhibition of glutamate uptake selectively prolongs the decay kinetics of the second field excitatory postsynaptic potential evoked by paired pulse stimulation of Schaffer collateral axons in area CA1. The model includes AMPA and NMDA glutamate receptors, and the removal of glutamate by transporters and diffusion. We establish analytically that the prolongation cannot be caused by local …

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Single Mutation To A Sex Pheromone Receptor Provides Adaptive Specificity Between Closely Related Moth Species, Gregory Patrick Leary, Jean E. Allen, Peggy L. Bunger, Jena B. Luginbill, Charles E. Linn Jr., Irene E. Macallister, Michael Kavanaugh, Kevin W. Wanner Jan 2012

Single Mutation To A Sex Pheromone Receptor Provides Adaptive Specificity Between Closely Related Moth Species, Gregory Patrick Leary, Jean E. Allen, Peggy L. Bunger, Jena B. Luginbill, Charles E. Linn Jr., Irene E. Macallister, Michael Kavanaugh, Kevin W. Wanner

Biomedical and Pharmaceutical Sciences Faculty Publications

Sex pheromone communication, acting as a prezygotic barrier to mating, is believed to have contributed to the speciation of moths and butterflies in the order Lepidoptera. Five decades after the discovery of the first moth sex pheromone, little is known about the molecular mechanisms that underlie the evolution of pheromone communication between closely related species. Although Asian and European corn borers (ACB and ECB) can be interbred in the laboratory, they are behaviorally isolated from mating naturally by their responses to subtly different sex pheromone isomers, (E)-12- and (Z)-12-tetradecenyl acetate and (E)-11- and (Z)-11-tetradecenyl acetate (ACB: E12, Z12; ECB; E11, …

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Functional Characterization And Analgesic Effects Of Mixed Cannabinoid Receptor/T-Type Channel Ligands, Haitao You, Vinicius M. Gadotti, Ravil R. Petrov, Gerald W. Zamponi, Philippe Diaz Nov 2011

Functional Characterization And Analgesic Effects Of Mixed Cannabinoid Receptor/T-Type Channel Ligands, Haitao You, Vinicius M. Gadotti, Ravil R. Petrov, Gerald W. Zamponi, Philippe Diaz

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity. Results: Novel compounds were characterized in radioligand binding assays and in vitro functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. …

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Specificity And Actions Of An Arylaspartate Inhibitor Of Glutamate Transport At The Schaffer Collateral-Ca1 Pyramidal Cell Synapse, Weinan Sun, Katie M. Hoffman, David C. Holley, Michael P. Kavanaugh Aug 2011

Specificity And Actions Of An Arylaspartate Inhibitor Of Glutamate Transport At The Schaffer Collateral-Ca1 Pyramidal Cell Synapse, Weinan Sun, Katie M. Hoffman, David C. Holley, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

In this study we characterized the pharmacological selectivity and physiological actions of a new arylaspartate glutamate transporter blocker, L-threo-beta-benzylaspartate (L-TBA). At concentrations up to 100 mu M, L-TBA did not act as an AMPA receptor (AMPAR) or NMDA receptor (NMDAR) agonist or antagonist when applied to outside-out patches from mouse hippocampal CA1 pyramidal neurons. L-TBA had no effect on the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded at the Schaffer collateral-CA1 pyramidal cell synapse. Excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons were unaffected by L-TBA in the presence of physiological extracellular Mg(2+) concentrations, but in Mg(2+)-free solution, EPSCs …

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Specificity And Actions Of An Arylaspartate Inhibitor Of Glutamate Transport At The Schaffer Collateral-Ca1 Pyramidal Cell Synapse, Weinan Sun, Katie Hoffman, David C. Holley, Michael P. Kavanaugh Aug 2011

Specificity And Actions Of An Arylaspartate Inhibitor Of Glutamate Transport At The Schaffer Collateral-Ca1 Pyramidal Cell Synapse, Weinan Sun, Katie Hoffman, David C. Holley, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

In this study we characterized the pharmacological selectivity and physiological actions of a new arylaspartate glutamate transporter blocker, L-threo-ß-benzylaspartate (L-TBA). At concentrations up to 100 µM, L-TBA did not act as an AMPA receptor (AMPAR) or NMDA receptor (NMDAR) agonist or antagonist when applied to outside-out patches from mouse hippocampal CA1 pyramidal neurons. L-TBA had no effect on the amplitude of field excitatory postsynaptic potentials (fEPSPs) recorded at the Schaffer collateral-CA1 pyramidal cell synapse. Excitatory postsynaptic currents (EPSCs) in CA1 pyramidal neurons were unaffected by L-TBA in the presence of physiological extracellular Mg2+ concentrations, but in Mg2+-free solution, EPSCs were …

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From Good Intentions To Proven Interventions: Effectiveness Of Actions To Reduce The Health Impacts Of Air Pollution, Luisa V. Giles, Prabjit Barn, Nino Kuenzli, Isabelle Romieu, Murray A. Mittleman, Stephan Van Eeden, Ryan Allen, Chris Carlsten, Dave Stieb, Curtis W. Noonan, Audrey Smargiassi, Joel D. Kaufman, Shakoor Hajat, Tom Kosatsky, Michael Brauer Jan 2011

From Good Intentions To Proven Interventions: Effectiveness Of Actions To Reduce The Health Impacts Of Air Pollution, Luisa V. Giles, Prabjit Barn, Nino Kuenzli, Isabelle Romieu, Murray A. Mittleman, Stephan Van Eeden, Ryan Allen, Chris Carlsten, Dave Stieb, Curtis W. Noonan, Audrey Smargiassi, Joel D. Kaufman, Shakoor Hajat, Tom Kosatsky, Michael Brauer

Biomedical and Pharmaceutical Sciences Faculty Publications

BACKGROUND: Associations between air pollution and a multitude of health effects are now well established. Given ubiquitous exposure to some level of air pollution, the attributable health burden can be high, particularly for susceptible populations. OBJECTIVES: An international multidisciplinary workshop was convened to discuss evidence of the effectiveness of actions to reduce health impacts of air pollution at both the community and individual level. The overall aim was to summarize current knowledge regarding air pollution exposure and health impacts leading to public health recommendations. DISCUSSION: During the workshop, experts reviewed the biological mechanisms of action of air pollution in the …

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The Central Cavity In Trimeric Glutamate Transporters Restricts Ligand Diffusion, Gregory Patrick Leary, David Charles Holley, Emily F. Stone, Brent Russell Lyda, Leonid Kalachev, Michael Kavanaugh Jan 2011

The Central Cavity In Trimeric Glutamate Transporters Restricts Ligand Diffusion, Gregory Patrick Leary, David Charles Holley, Emily F. Stone, Brent Russell Lyda, Leonid Kalachev, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

A prominent aqueous cavity is formed by the junction of three identical subunits in the excitatory amino acid transporter (EAAT) family. To investigate the effect of this structure on the interaction of ligands with the transporter, we recorded currents in voltage-clamped Xenopus oocytes expressing EAATs and used concentration jumps to measure binding and unbinding rates of a high-affinity aspartate analog that competitively blocks transport (β-2-fluorenyl-aspartylamide; 2-FAA). The binding rates of the blocker were approximately one order of magnitude slower than l-Glu and were not significantly different for EAAT1, EAAT2, or EAAT3, but 2-FAA exhibited higher affinity for the neuronal transporter …

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Organophosphorus Pesticides Decrease M2 Muscarinic Receptor Function In Guinea Pig Airway Nerves Via Indirect Mechanisms, Becky J. Proskocil, Donald A. Bruun, Charles M. Thompson, Allison D. Fryer, Pamela J. Lein May 2010

Organophosphorus Pesticides Decrease M2 Muscarinic Receptor Function In Guinea Pig Airway Nerves Via Indirect Mechanisms, Becky J. Proskocil, Donald A. Bruun, Charles M. Thompson, Allison D. Fryer, Pamela J. Lein

Biomedical and Pharmaceutical Sciences Faculty Publications

Background: Epidemiological studies link organophosphorus pesticide (OP) exposures to asthma, and we have shown that the OPs chlorpyrifos, diazinon and parathion cause airway hyperreactivity in guinea pigs 24 hr after a single subcutaneous injection. OP-induced airway hyperreactivity involves M2 muscarinic receptor dysfunction on airway nerves independent of acetylcholinesterase (AChE) inhibition, but how OPs inhibit neuronal M2 receptors in airways is not known. In the central nervous system, OPs interact directly with neurons to alter muscarinic receptor function or expression; therefore, in this study we tested whether the OP parathion or its oxon metabolite, paraoxon, might decrease M2 receptor function on …

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Mass Spectrometric Analyses Of Organophosphate Insecticide Oxon Protein Adducts, Charles M. Thompson, John M. Prins, Kathleen M. George Jan 2010

Mass Spectrometric Analyses Of Organophosphate Insecticide Oxon Protein Adducts, Charles M. Thompson, John M. Prins, Kathleen M. George

Biomedical and Pharmaceutical Sciences Faculty Publications

OBJECTIVE: Organophosphate (OP) insecticides continue to be used to control insect pests. Acute and chronic exposures to OP insecticides have been documented-to cause adverse health effects, but few OP-adducted proteins have been correlated with these illnesses at the molecular level. Our aim was to review the literature covering the current state of the art in mass spectrometry (MS) used to identify OP protein biomarkers. DATA SOURCES AND EXTRACTION: We identified general and specific research reports related to OP insecticides, OP toxicity, OP structure, and protein MS by searching PubMed and Chemical Abstracts for articles published before December 2008. DATA SYNTHESIS: …

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Assembly Of Arenavirus Envelope Glycoprotein Gpc In Detergent-Soluble Membrane Microdomains, Sudhakar S. Agnihothram, Brooke Dancho, Kenneth W. Grant, Mark L. Grimes, Douglas S. Lyles, Jack H. Nunberg Oct 2009

Assembly Of Arenavirus Envelope Glycoprotein Gpc In Detergent-Soluble Membrane Microdomains, Sudhakar S. Agnihothram, Brooke Dancho, Kenneth W. Grant, Mark L. Grimes, Douglas S. Lyles, Jack H. Nunberg

Biomedical and Pharmaceutical Sciences Faculty Publications

The family Arenaviridae includes a number of highly pathogenic viruses that are responsible for acute hemorrhagic fevers in humans. Genetic diversity among arenavirus species in their respective rodent hosts supports the continued emergence of new pathogens. In the absence of available vaccines or therapeutic agents, the hemorrhagic fever arenaviruses remain a serious public health and biodefense concern. Arenaviruses are enveloped virions that assemble and bud from the plasma membrane. In this study, we have characterized the microdomain organization of the virus envelope glycoprotein (GPC) on the cell surface by using immunogold electron microscopy. We find that Junin virus (JUNV) GPC …

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Interactions Of Alkali Cations With Glutamate Transporters, David C. Holley, Michael P. Kavanaugh Jan 2009

Interactions Of Alkali Cations With Glutamate Transporters, David C. Holley, Michael P. Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

The transport of glutamate is coupled to the co-transport of three Na+ ions and the countertransport of one K+ ion. In addition to this carrier-type exchange behaviour, glutamate transporters also behave as chloride channels. The chloride channel activity is strongly influenced by the cations that are involved in coupled flux, making glutamate transporters representative of the ambiguous interface between carriers and channels. In this paper, we review the interaction of alkali cations with glutamate transporters in terms of these diverse functions. We also present a model derived from electrostatic mapping of the predicted cation-binding sites in the X-ray crystal structure …

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Urinary Levoglucosan As A Biomarker Of Wood Smoke Exposure: Observations In A Mouse Model And In Children, Christopher T. Migliaccio, M. A. Bergauff, Christopher P. Palmer, Forrest Jessop, Curtis W. Noonan, Tony Ward Jan 2009

Urinary Levoglucosan As A Biomarker Of Wood Smoke Exposure: Observations In A Mouse Model And In Children, Christopher T. Migliaccio, M. A. Bergauff, Christopher P. Palmer, Forrest Jessop, Curtis W. Noonan, Tony Ward

Biomedical and Pharmaceutical Sciences Faculty Publications

BACKGROUND: Biomass smoke is an important source of particulate matter (PM), and much remains to be discovered with respect to the human health effects associated with this specific PM source. Exposure to biomass smoke can occur in one of two main categories: short-term exposures consist of periodic, seasonal exposures typified by communities near forest fires or intentional agricultural burning, and long-term exposures are chronic and typified by the use of biomass materials for cooking or heating. Levoglucosan (LG), a sugar anhydride released by combustion of cellulose-containing materials, is an attractive candidate as a biomarker of wood smoke exposure. OBJECTIVES: In …

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Neurovirulence Of Polytropic Murine Retrovirus Is Influenced By Two Separate Regions On Opposite Sides Of The Envelope Protein Receptor Binding Domain, Karin E. Peterson, Susan Pourciau, Min Du, Rachel Lacasse, Melissa Pathmajeyan, David J. Poulsen, Mavis Agbandje-Mckenna, Kathy Wehrly, Bruce Chesebro Sep 2008

Neurovirulence Of Polytropic Murine Retrovirus Is Influenced By Two Separate Regions On Opposite Sides Of The Envelope Protein Receptor Binding Domain, Karin E. Peterson, Susan Pourciau, Min Du, Rachel Lacasse, Melissa Pathmajeyan, David J. Poulsen, Mavis Agbandje-Mckenna, Kathy Wehrly, Bruce Chesebro

Biomedical and Pharmaceutical Sciences Faculty Publications

Changes in the envelope proteins of retroviruses can alter the ability of these viruses to infect the central nervous system (CNS) and induce neurological disease. In the present study, nine envelope residues were found to influence neurovirulence of the Friend murine polytropic retrovirus Fr98. When projected on a three-dimensional model, these residues were clustered in two spatially separated groups, one in variable region B of the receptor binding site and the other on the opposite side of the envelope. Further studies indicated a role for these residues in virus replication in the CNS, although the residues did not affect viral …

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The Glutamate And Chloride Permeation Pathways Are Colocalized In Individual Neuronal Glutamate Transporter Subunits, Gregory Patrick Leary, Emily F. Stone, David Charles Holley, Michael Kavanaugh Jan 2007

The Glutamate And Chloride Permeation Pathways Are Colocalized In Individual Neuronal Glutamate Transporter Subunits, Gregory Patrick Leary, Emily F. Stone, David Charles Holley, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Glutamate transporters have a homotrimeric subunit structure with a large central water-filled cavity that extends partially into the plane of the lipid bilayer (Yernool et al., 2004). In addition to uptake of glutamate, the transporters also mediate a chloride conductance that is increased in the presence of substrate. Whether the chloride channel is located in the central pore of the trimer or within the individual subunits has been controversial. We find that coexpression of wild-type neuronal glutamate transporter EAAT3 subunits with subunits mutated at R447, a residue governing substrate selectivity (Bendahan et al., 2000), results in …

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Appl1 Associates With Trka And Gipc1 And Is Required For Nerve Growth Factor-Mediated Signal Transduction, D. C. Lin, C. Quevedo, N. E. Brewer, A. Bell, J. R. Testa, Mark L. Grimes, F. D. Miller, D. R. Kaplan Dec 2006

Appl1 Associates With Trka And Gipc1 And Is Required For Nerve Growth Factor-Mediated Signal Transduction, D. C. Lin, C. Quevedo, N. E. Brewer, A. Bell, J. R. Testa, Mark L. Grimes, F. D. Miller, D. R. Kaplan

Biomedical and Pharmaceutical Sciences Faculty Publications

The neurotrophin receptor TrkA plays critical roles in the nervous system by recruiting signaling molecules that activate pathways required for the growth and survival of neurons. Here, we report APPL1 as a TrkA-associated protein. APPL1 and TrkA coirnmunoprecipitated in sympathetic neurons. We have identified two routes through which this association can occur. APPL1 was isolated as a binding partner for the TrkA-interacting protein GIPC1 from rat brain lysate by mass spectrometry. The PDZ domain of GIPC1 directly engaged the C-terminal sequence of APPL1. This interaction provides a means through which APPL1 may be recruited to TrkA. In addition, the APPL1 …

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Nested Case-Control Study Of Autoimmune Disease In An Asbestos-Exposed Population, Curis W. Noonan, Jean C. Pfau, Theodore C. Larson, Michael R. Spence Aug 2006

Nested Case-Control Study Of Autoimmune Disease In An Asbestos-Exposed Population, Curis W. Noonan, Jean C. Pfau, Theodore C. Larson, Michael R. Spence

Biomedical and Pharmaceutical Sciences Faculty Publications

OBJECTIVE: To explore the potential association between asbestos exposure and risk of autoimmmune disease, we conducted a case-control study among a cohort of 7,307 current and former residents of Libby, Montana, a community with historical occupational and environmental exposure to asbestos-contaminated vermiculite. METHODS: Cases were defined as those who reported having one of three systemic autoimmune diseases (SAIDs): systemic lupus erythematosus, scleroderma, or rheumatoid arthritis (RA). Controls were randomly selected at a 3:1 ratio from among the remaining 6,813 screening participants using frequency-matched age and sex groupings. RESULTS: The odds ratios (ORs) and 95% confidence intervals (CIs) for SAIDs among …

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Assessment Of Autoimmune Responses Associated With Asbestos Exposure In Libby, Montana, Usa, Jean C. Pfau, J. J. Sentissi, G. Weller, Elizabeth Putnam Jan 2005

Assessment Of Autoimmune Responses Associated With Asbestos Exposure In Libby, Montana, Usa, Jean C. Pfau, J. J. Sentissi, G. Weller, Elizabeth Putnam

Biomedical and Pharmaceutical Sciences Faculty Publications

Systemic autoimmune responses are associated with certain environmental exposures, including crystalline particles such as silica. Positive antinuclear antibody (ANA) tests have been reported in small cohorts exposed to asbestos, but many questions remain regarding the prevalence, pattern, and significance of autoantibodies associated with asbestos exposures. The population in Libby, Montana, provides a unique opportunity for such a study because of both occupational and environmental exposures that have occurred as a result of the mining of asbestos-contaminated vermiculite near the community. As part of a multifaceted assessment of the impact of asbestos exposures on this population, this study explored the possibility …

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Fluorometric Measurements Of Conformational Changes In Glutamate Transporters, H. Peter Larsson, Anastassios V. Tzingounis, Hans-Peter Koch, Michael Kavanaugh Jan 2004

Fluorometric Measurements Of Conformational Changes In Glutamate Transporters, H. Peter Larsson, Anastassios V. Tzingounis, Hans-Peter Koch, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Glutamate transporters remove glutamate from the synaptic cleft to maintain efficient synaptic communication between neurons and to prevent extracellular glutamate concentrations from reaching neurotoxic levels (1). It is thought that glutamate transporters mediate glutamate transport through a reaction cycle with conformational changes between the two major access states that alternatively expose glutamate-binding sites to the extracellular or to the intracellular solution. However, there is no direct real-time evidence for the conformational changes predicted to occur during the transport cycle. In the present study, we used voltage-clamp fluorometry to measure conformational changes in the neuronal excitatory amino acid transporter …

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Equilibrative Nucleoside Transporter Family Members From Leishmania Donovani Are Electrogenic Proton Symporters, Alex Stein, Gayatri Vaseduvan, Nicola S. Carter, Buddy Ullman, Scott M. Landfear, Michael Kavanaugh Jan 2003

Equilibrative Nucleoside Transporter Family Members From Leishmania Donovani Are Electrogenic Proton Symporters, Alex Stein, Gayatri Vaseduvan, Nicola S. Carter, Buddy Ullman, Scott M. Landfear, Michael Kavanaugh

Biomedical and Pharmaceutical Sciences Faculty Publications

Leishmania donovani express two members of the equilibrative nucleoside transporter family; LdNT1 encoded by two closely related and linked genes, LdNT1.1 and LdNT1.2, that transport adenosine and pyrimidine nucleosides and LdNT2 that transports inosine and guanosine exclusively. LdNT1.1, LdNT1.2, and LdNT2 have been expressed in Xenopus laevis oocytes and found to be electrogenic in the presence of nucleoside ligands for which they mediate transport. Further analysis revealed that ligand uptake and transport currents through LdNT1-type transporters are proton-dependent. In addition to the flux of protons that is coupled to the transport reaction, LdNT1 transporters mediate a variable constitutive proton …

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Glutamine Uptake By Neurons: Interaction Of Protons With System A Transporters, Farrukh A. Chaudhry, Dietmar Schmitz, Richard J. Reimer, Peter Larsson, Andrew T. Gray, Roger Nicoll, Michael Kavanaugh, Robert H. Edwards Jan 2002

Glutamine Uptake By Neurons: Interaction Of Protons With System A Transporters, Farrukh A. Chaudhry, Dietmar Schmitz, Richard J. Reimer, Peter Larsson, Andrew T. Gray, Roger Nicoll, Michael Kavanaugh, Robert H. Edwards

Biomedical and Pharmaceutical Sciences Faculty Publications

Astrocytes provide the glutamine required by neurons to synthesize glutamate and GABA. However, the mechanisms involved in glutamine transfer from glia to neurons have remained poorly understood. Recent work has implicated the System N transporter SN1 in the efflux of glutamine from astrocytes and the very closely related System A transporters SA1 and SA2 in glutamine uptake by neurons. To understand how these closely related proteins mediate flux in different directions, we have examined their ionic coupling. In contrast to the electroneutral exchange of H+ for Na+ and neutral amino acid catalyzed by SN1, we now show that …

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