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Articles 31 - 60 of 78
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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
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 …
Mass Spectrometric Analyses Of Organophosphate Insecticide Oxon Protein Adducts, Charles M. Thompson, John M. Prins, Kathleen M. George
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: …
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
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 …
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
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 …
Interactions Of Alkali Cations With Glutamate Transporters, David C. Holley, Michael P. Kavanaugh
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 …
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
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 …
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
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 …
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
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 …
Nested Case-Control Study Of Autoimmune Disease In An Asbestos-Exposed Population, Curis W. Noonan, Jean C. Pfau, Theodore C. Larson, Michael R. Spence
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 …
Assessment Of Autoimmune Responses Associated With Asbestos Exposure In Libby, Montana, Usa, Jean C. Pfau, J. J. Sentissi, G. Weller, Elizabeth Putnam
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 …
Fluorometric Measurements Of Conformational Changes In Glutamate Transporters, H. Peter Larsson, Anastassios V. Tzingounis, Hans-Peter Koch, Michael Kavanaugh
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 …
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
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 …
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
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 …
Dynamic Equilibrium Between Coupled And Uncoupled Modes Of A Neuronal Glutamate Transporter, Lars Borre, Michael Kavanaugh, Baruch I. Kanner
Dynamic Equilibrium Between Coupled And Uncoupled Modes Of A Neuronal Glutamate Transporter, Lars Borre, Michael Kavanaugh, Baruch I. Kanner
Biomedical and Pharmaceutical Sciences Faculty Publications
In the brain, the neurotransmitter glutamate is removed from the synaptic cleft by (Na+ + K+)-coupled transporters by an electrogenic process. Moreover, these transporters mediate a sodium- and glutamate-dependent uncoupled chloride conductance. In contrast to the wild type, the uptake of radiolabeled substrate by the I421C mutant is inhibited by the membrane-impermeant [2-(trimethylammonium)ethyl]methanethiosulfonate and also by other sulfhydryl reagents. In the wild-type and the unmodified mutant, substrate-induced currents are inwardly rectifying and reflect the sum of the coupled electrogenic flux and the anion conductance. Remarkably, the I421C mutant modified by sulfhydryl reagents exhibits currents that are non-rectifying …
Truncated Forms Of The Dual Function Human Asct2 Neutral Amino Acid Transporter/Retroviral Receptor Are Translationally Initiated At Multiple Alternative Cug And Gug Codons, Chetankumar S. Tailor, Mariana Marin, Ali Nouri, Michael Kavanaugh, David Kabat
Truncated Forms Of The Dual Function Human Asct2 Neutral Amino Acid Transporter/Retroviral Receptor Are Translationally Initiated At Multiple Alternative Cug And Gug Codons, Chetankumar S. Tailor, Mariana Marin, Ali Nouri, Michael Kavanaugh, David Kabat
Biomedical and Pharmaceutical Sciences Faculty Publications
The sodium-dependent neutral amino acid transporter type 2 (ASCT2) was recently identified as a cell surface receptor for endogenously inherited retroviruses of cats, baboons, and humans as well as for horizontally transmitted type-D simian retroviruses. By functional cloning, we obtained 10 full-length 2.9-kilobase pair (kbp) cDNAs and two smaller identical 2.1-kbp cDNAs that conferred susceptibility to these viruses. Compared with the 2.9-kbp cDNA, the 2.1-kbp cDNA contains exonic deletions in its 3′ noncoding region and a 627-bp 5′ truncation that eliminates sequences encoding the amino-terminal portion of the full-length ASCT2 protein. Although expression of the truncated mRNA caused enhanced amino …
Isolation Of Current Components And Partial Reaction Cycles In The Glial Glutamate Transporter Eaat2, Thomas S. Otis, Michael Kavanaugh
Isolation Of Current Components And Partial Reaction Cycles In The Glial Glutamate Transporter Eaat2, Thomas S. Otis, Michael Kavanaugh
Biomedical and Pharmaceutical Sciences Faculty Publications
The kinetic properties of the excitatory amino acid transporter EAAT2 were studied using rapid applications of l-glutamate to outside-out patches excised from transfected human embryonic kidney 293 cells. In the presence of the highly permeant anion SCN−, pulses of glutamate rapidly activated transient anion channel currents mediated by the transporter. In the presence of the impermeant anion gluconate, glutamate pulses activated smaller currents predicted to result from stoichiometric flux of cotransported ions. Both anion and stoichiometric currents displayed similar kinetics, suggesting that anion channel gating and stoichiometric charge movements are linked to early transitions in the transport cycle. …
Arginine 447 Plays A Pivotal Role In Substrate Interactions In A Neuronal Glutamate Transporter, Annie Bendahan, Ayelet Armon, Navid Madani, Michael Kavanaugh, Baruch I. Kanner
Arginine 447 Plays A Pivotal Role In Substrate Interactions In A Neuronal Glutamate Transporter, Annie Bendahan, Ayelet Armon, Navid Madani, Michael Kavanaugh, Baruch I. Kanner
Biomedical and Pharmaceutical Sciences Faculty Publications
Glutamate transporters from the central nervous system play a crucial role in the clearance of the transmitter from the synaptic cleft. Glutamate is cotransported with sodium ions, and the electrogenic translocation cycle is completed by countertransport of potassium. Mutants that cannot interact with potassium are only capable of catalyzing electroneutral exchange. Here we identify a residue involved in controlling substrate recognition in the neuronal transporter EAAC-1 that transports acidic amino acids as well as cysteine. When arginine 447, a residue conserved in all glutamate transporters, is replaced by cysteine, transport of glutamate or aspartate is abolished, but sodium-dependent cysteine transport …
Pentameric Assembly Of A Neuronal Glutamate Transporter, Sepehr Eskandari, Michael Kreman, Michael Kavanaugh, Ernest M. Wright, Guido A. Zampighi
Pentameric Assembly Of A Neuronal Glutamate Transporter, Sepehr Eskandari, Michael Kreman, Michael Kavanaugh, Ernest M. Wright, Guido A. Zampighi
Biomedical and Pharmaceutical Sciences Faculty Publications
Freeze-fracture electron microscopy was used to study the structure of a human neuronal glutamate transporter (EAAT3). EAAT3 was expressed in Xenopus laevis oocytes, and its function was correlated with the total number of transporters in the plasma membrane of the same cells. Function was assayed as the maximum charge moved in response to a series of transmembrane voltage pulses. The number of transporters in the plasma membrane was determined from the density of a distinct 10-nm freeze-fracture particle, which appeared in the protoplasmic face only after EAAT3 expression. The linear correlation between EAAT3 maximum carrier-mediated charge and the total number …
A Critical Site In The Core Of The Ccr5 Chemokine Receptor Required For Binding And Infectivity Of Human Immunodeficiency Virus Type 1, Salvatore J. Siciliano, Shawn E. Kuhmann, Youmin Weng, Navid Madani, Martin S. Springer, Janet E. Lineberger, Renee Danzeisen, Michael D. Miller, Michael Kavanaugh, Julie A. Demartino, David Kabat
A Critical Site In The Core Of The Ccr5 Chemokine Receptor Required For Binding And Infectivity Of Human Immunodeficiency Virus Type 1, Salvatore J. Siciliano, Shawn E. Kuhmann, Youmin Weng, Navid Madani, Martin S. Springer, Janet E. Lineberger, Renee Danzeisen, Michael D. Miller, Michael Kavanaugh, Julie A. Demartino, David Kabat
Biomedical and Pharmaceutical Sciences Faculty Publications
Like the CCR5 chemokine receptors of humans and rhesus macaques, the very homologous (∼98–99% identical) CCR5 of African green monkeys (AGMs) avidly binds β-chemokines and functions as a coreceptor for simian immunodeficiency viruses. However, AGM CCR5 is a weak coreceptor for tested macrophage-tropic (R5) isolates of human immunodeficiency virus type 1 (HIV-1). Correspondingly, gp120 envelope glycoproteins derived from R5 isolates of HIV-1 bind poorly to AGM CCR5. We focused on a unique extracellular amino acid substitution at the juncture of transmembrane helix 4 (TM4) and extracellular loop 2 (ECL2) (Arg for Gly at amino acid 163 (G163R)) as the likely …
Arachidonic Acid Activates A Proton Current In The Rat Glutamate Transporter Eaat4, Anastassios V. Tzingounis, Chien-Liang Lin, Jeffrey D. Rothstein, Michael Kavanaugh
Arachidonic Acid Activates A Proton Current In The Rat Glutamate Transporter Eaat4, Anastassios V. Tzingounis, Chien-Liang Lin, Jeffrey D. Rothstein, Michael Kavanaugh
Biomedical and Pharmaceutical Sciences Faculty Publications
The excitatory amino acid transporter EAAT4 is expressed predominantly in Purkinje neurons in the rat cerebellum (1-3), and it participates in postsynaptic reuptake of glutamate released at the climbing fiber synapse (4). Transporter-mediated currents in Purkinje neurons are increased more than 3-fold by arachidonic acid, a second messenger that is liberated following depolarization-induced Ca2+ activation of phospholipase A2 (5). In this study we demonstrate that application of arachidonic acid to oocytes expressing rat EAAT4 increased glutamate-induced currents to a similar extent. However, arachidonic acid did not cause an increase in the rate …
Macroscopic And Microscopic Properties Of A Cloned Glutamate Transporter/Chloride Channel, Jacques I. Wadiche, Michael Kavanaugh
Macroscopic And Microscopic Properties Of A Cloned Glutamate Transporter/Chloride Channel, Jacques I. Wadiche, Michael Kavanaugh
Biomedical and Pharmaceutical Sciences Faculty Publications
The behavior of a Cl− channel associated with a glutamate transporter was studied using intracellular and patch recording techniques in Xenopus oocytes injected with human EAAT1 cRNA. Channels could be activated by application of glutamate to either face of excised membrane patches. The channel exhibited strong selectivity for amphipathic anions and had a minimum pore diameter of ∼5Å. Glutamate flux exhibited a much greater temperature dependence than Cl− flux. Stationary and nonstationary noise analysis was consistent with a sub-femtosiemen Cl− conductance and a maximum channelPo ≪ 1. The glutamate binding rate was similar to estimates …
Neurotransmitter Transport: Models In Flux, Michael Kavanaugh
Neurotransmitter Transport: Models In Flux, Michael Kavanaugh
Biomedical and Pharmaceutical Sciences Faculty Publications
Physiologists say that ions and neutral solutes can cross biological membranes via “transporters” and “channels.” We tend to think about the difference between transporters and channels in terms of gating mechanisms. Ion channels exhibit a wide range of selectivity properties and permeation rates, but their gating at the most basic level can be thought of in terms of a single barrier or gate acting as a switch. When the gate is closed, ions can’t permeate; when the gate is opened, a permeation pathway for ions allows flux, often at very high rates (up to 108/sec). Transporters and ion …
Gp120 Envelope Glycoproteins Of Human Immunodeficiency Viruses Competitively Antagonize Signaling By Coreceptors Cxcr4 And Ccr5, Navid Madani, Susan L. Kozak, Michael Kavanaugh, David Kabat
Gp120 Envelope Glycoproteins Of Human Immunodeficiency Viruses Competitively Antagonize Signaling By Coreceptors Cxcr4 And Ccr5, Navid Madani, Susan L. Kozak, Michael Kavanaugh, David Kabat
Biomedical and Pharmaceutical Sciences Faculty Publications
Signal transductions by the dual-function CXCR4 and CCR5 chemokine receptors/HIV type 1 (HIV-1) coreceptors were electrophysiologically monitored in Xenopus laevis oocytes that also coexpressed the viral receptor CD4 and a G protein-coupled inward-rectifying K+ channel (Kir 3.1). Large Kir 3.1-dependent currents generated in response to the corresponding chemokines (SDF-1α for CXCR4 and MIP-1α; MIP-1β and RANTES for CCR5) were blocked by pertussis toxin, suggesting involvement of inhibitory guanine nucleotide-binding proteins. Prolonged exposures to chemokines caused substantial but incomplete desensitization of responses with time constants of 5–7 min and recovery time constants of 12–19 min. CXCR4 and CCR5 exhibited heterologous …
Cysteine Scanning Of The Surroundings Of An Alkali-Ion Binding Site Of The Glutamate Transporter Glt-1 Reveals A Conformationally Sensitive Residue, Ruth Zarbiv, Myriam Grunewald, Michael Kavanaugh, Baruch I. Kanner
Cysteine Scanning Of The Surroundings Of An Alkali-Ion Binding Site Of The Glutamate Transporter Glt-1 Reveals A Conformationally Sensitive Residue, Ruth Zarbiv, Myriam Grunewald, Michael Kavanaugh, Baruch I. Kanner
Biomedical and Pharmaceutical Sciences Faculty Publications
Glutamate transporters remove this transmitter from the extracellular space by cotransport with three sodium ions and a proton. The cycle is completed by translocation of a potassium ion in the opposite direction. Recently we have identified two adjacent amino acid residues of the glutamate transporter GLT-1 that influence potassium coupling. Using the scanning cysteine accessibility method we have now explored the highly conserved region surrounding them. Replacement of each of the five consecutive residues 396–400 by cysteine abolished transport activity but at several other positions the substitution is tolerated. One residue, tyrosine 403, was identified where cysteine substitution renders the …
Molecular Determinant Of Ion Selectivity Of A (Na+ + K+)-Coupled Rat Brain Glutamate Transporter, Yumin Zhang, Annie Bendahan, Ruth Zarbiv, Michael Kavanaugh, Baruch I. Kanner
Molecular Determinant Of Ion Selectivity Of A (Na+ + K+)-Coupled Rat Brain Glutamate Transporter, Yumin Zhang, Annie Bendahan, Ruth Zarbiv, Michael Kavanaugh, Baruch I. Kanner
Biomedical and Pharmaceutical Sciences Faculty Publications
Glutamate transporters remove this neurotransmitter from the synaptic cleft by a two-stage electrogenic process, in which glutamate is first cotransported with three sodium ions and a proton. Subsequently, the cycle is completed by translocation of a potassium ion in the opposite direction. Recently, we have identified an amino acid residue of the glutamate transporter GLT-1 (Glu-404) that influences potassium coupling. We have now analyzed the effect of seven other amino acid residues in the highly conserved region surrounding this site. One of these residues, Tyr-403, also proved important for potassium coupling, because mutation to Phe (Y403F) resulted in an electroneutral …
Excitatory Amino Acid Transporters Of The Salamander Retina: Identification, Localization, And Function, Scott Eliasof, Jeffrey L. Arriza, Barbara H. Leighton, Michael Kavanaugh, Susan G. Amara
Excitatory Amino Acid Transporters Of The Salamander Retina: Identification, Localization, And Function, Scott Eliasof, Jeffrey L. Arriza, Barbara H. Leighton, Michael Kavanaugh, Susan G. Amara
Biomedical and Pharmaceutical Sciences Faculty Publications
The rapid re-uptake of extracellular glutamate mediated by a family of high-affinity glutamate transporter proteins is essential to continued glutamatergic signaling and neuronal viability, but the contributions of individual transporter subtypes toward cellular physiology are poorly understood. Because the physiology of glutamate transport in the salamander retina has been well described, we have examined the expression and function of glutamate transporter subtypes in this preparation. cDNAs encoding five distinct salamander excitatory amino acid transporter (sEAAT) subtypes were isolated, and their molecular properties and distributions of expression were compared. We report evidence that at least four distinct sEAAT subtypes are expressed …
Tyrosine 140 Of The Γ-Aminobutyric Acid Transporter Gat-1 Plays A Critical Role In Neurotransmitter Recognition, Yona Bismuth, Michael Kavanaugh, Baruch I. Kanner
Tyrosine 140 Of The Γ-Aminobutyric Acid Transporter Gat-1 Plays A Critical Role In Neurotransmitter Recognition, Yona Bismuth, Michael Kavanaugh, Baruch I. Kanner
Biomedical and Pharmaceutical Sciences Faculty Publications
The γ-aminobutyric acid (GABA) transporter GAT-1 is located in nerve terminals and catalyzes the electrogenic reuptake of the neurotransmitter with two sodium ions and one chloride. We now identify a single tyrosine residue that is critical for GABA recognition and transport. It is completely conserved throughout the superfamily, and even substitution to the other aromatic amino acids, phenylalanine (Y140F) and tryptophan (Y140W), results in completely inactive transporters. Electrophysiological characterization reveals that both mutant transporters exhibit the sodium-dependent transient currents associated with sodium binding as well as the chloride-dependent lithium leak currents characteristic of GAT-1. On the other hand, in both …
Mutation Of An Amino Acid Residue Influencing Potassium Coupling In The Glutamate Transporter Glt-1 Induces Obligate Exchange, Michael Kavanaugh, Annie Bendahan, Noa Zerangue, Yumin Zhang, Baruch I. Kanner
Mutation Of An Amino Acid Residue Influencing Potassium Coupling In The Glutamate Transporter Glt-1 Induces Obligate Exchange, Michael Kavanaugh, Annie Bendahan, Noa Zerangue, Yumin Zhang, Baruch I. Kanner
Biomedical and Pharmaceutical Sciences Faculty Publications
Glutamate transporters maintain low synaptic concentrations of neurotransmitter by coupling uptake to flux of other ions. After cotransport of glutamic acid with Na+, the cycle is completed by countertransport of K+. We have identified an amino acid residue (glutamate 404) influencing ion coupling in a domain of the transporter implicated previously in kainate binding. Mutation of this residue to aspartate (E404D) prevents both forward and reverse transport induced by K+. Sodium-dependent transmitter exchange and a transporter-mediated chloride conductance are unaffected by the mutation, indicating that this residue selectively influences potassium flux coupling. The results …
Excitatory Amino Acid Transporter 5, A Retinal Glutamate Transporter Coupled To A Chloride Conductance, Jeffrey L. Arriza, Scott Eliasof, Michael Kavanaugh, Susan G. Amara
Excitatory Amino Acid Transporter 5, A Retinal Glutamate Transporter Coupled To A Chloride Conductance, Jeffrey L. Arriza, Scott Eliasof, Michael Kavanaugh, Susan G. Amara
Biomedical and Pharmaceutical Sciences Faculty Publications
Although a glutamate-gated chloride conductance with the properties of a sodium-dependent glutamate transporter has been described in vertebrate retinal photoreceptors and bipolar cells, the molecular species underlying this conductance has not yet been identified. We now report the cloning and functional characterization of a human excitatory amino acid transporter, EAAT5, expressed primarily in retina. Although EAAT5 shares the structural homologies of the EAAT gene family, one novel feature of the EAAT5 sequence is a carboxy-terminal motif identified previously in N-methyl-d-aspartate receptors and potassium channels and shown to confer interactions with a family of synaptic proteins that promote ion channel …
Multiple Ionic Conductances Of The Human Dopamine Transporter: The Actions Of Dopamine And Psychostimulants, Mark S. Sonders, Si-Jia Zhu, Nancy R. Zahniser, Michael Kavanaugh, Susan G. Amara
Multiple Ionic Conductances Of The Human Dopamine Transporter: The Actions Of Dopamine And Psychostimulants, Mark S. Sonders, Si-Jia Zhu, Nancy R. Zahniser, Michael Kavanaugh, Susan G. Amara
Biomedical and Pharmaceutical Sciences Faculty Publications
Electrophysiological and pharmacological studies of a cloned human dopamine transporter (hDAT) were undertaken to investigate the mechanisms of transporter function and the actions of drugs at this target. Using two-electrode voltage-clamp techniques with hDAT-expressing Xenopus laevis oocytes, we show that hDAT can be considered electrogenic by two criteria. (1) Uptake of hDAT substrates gives rise to a pharmacologically appropriate “transport-associated” current. (2) The velocity of DA uptake measured in oocytes clamped at various membrane potentials was voltage-dependent, increasing with hyperpolarization. Concurrent measurement of transport-associated current and substrate flux in individual oocytes revealed that charge movement during substrate translocation was greater …