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michael.kavanaugh

Profile

 

Name: Michael Kavanaugh

Title: Director, Center for Structural and Functional Neuroscience

Email: michael.kavanaugh@umontana.edu

Phone: 406-243-4398

Office: SB 390B

Lab Phone: 406-243-4718

Lab: SB 385

Background

After completing undergraduate work in Biology at Washington University in St. Louis in 1982, Michael Kavanaugh received his Ph.D. in Biochemistry from OHSU in 1987. He pursued a postdoctoral fellowship at the Vollum Institute and joined the Vollum faculty in 1993. Kavanaugh joined The University of Montana in January 2003, and is the Director of the COBRE Center for Structural and Functional Neuroscience.

 

Research Statement

Research in the Kavanaugh laboratory focuses on transporters and ion channels, membrane proteins involved in solute uptake and signaling in neurons and other cells. Kavanaugh and his associates integrate electrophysiological and molecular biological approaches in their work. Cloned transporters and channels are expressed in Xenopus oocytes or mammalian cells and studied using techniques including voltage-clamp recording, radiotracer flux measurement, and site-directed mutagenesis. Other studies are focused on the behavior of these molecules in native retinal neurons.

Elucidating the biophysical properties of ion channels and transporters is necessary for understanding the physiological roles of these molecules. In the brain, transporters mediate the reuptake of neurotransmitter following its release from the presynaptic cell. Kavanaugh and coworkers are particularly interested in the structural and functional properties of transporters for glutamate, the major central nervous system excitatory neurotransmitter. They are probing the molecular mechanisms involved in translocating glutamate across the cell membrane by examining flux of ions through the transporters as well as by analyzing the effects of mutations on this flux.

Glutamate transport is thermodynamically coupled to the cotransport of three sodium ions and one proton, and the countertransport of one potassium ion. However, a chloride channel is also associated with glutamate transporters and the channel open-probability increases when glutamate is present. The physiological role of this channel is unclear. Kavanaugh's lab is exploring its properties in terminals of retinal photoreceptors, where it may significantly influence the presynaptic membrane conductance. Another active area of research in the lab involves relating the chloride channel kinetics to glutamate transport kinetics. Understanding this relationship will allow the channel to be used to monitor the microscopic states of the transporter, providing a powerful tool for developing and testing kinetic models.

Other ongoing research involves studies of the tertiary and quaternary structures of glutamate transporters. Identification of residues involved in key functions such as ion selectivity and glutamate recognition are beginning to allow construction of more detailed models for the fundamental molecular processes involved in transporter gating and ion co- and countertransport. The oligomeric structure of the transporters is also being studied by coexpressing different proportions of wild-type transporter subunits together with mutant subunits with altered functional properties. Analysis of the resulting transport properties indicates that multiple subunits interact to form a functional complex. Functional modeling together with complementary biochemical studies are being used to define the subunit stoichiometry further.

 

Publications

Fairman, W.A., Vandenberg, R.J., Arriza, J.L., Kavanaugh, M.P., & Amara, S.G. (1995) An excitatory amino-acid transporter with properties of a ligand-gated chloride channel. Nature 375 599-603.

Wadiche, J.I., Arriza, J.L., Amara, S.G., & Kavanaugh, M.P. (1995) Kinetics of a human glutamate transporter. Neuron 14 1019-1027.

Vandenberg, R.J., Arriza, J.L., Amara, S.G., & Kavanaugh, M.P. (1995) Constitutive ion fluxes and substrate binding domains of human glutamate transporters.Biol Chem 270 17668-17671.

Wadiche, J.I., Amara, S.G., & Kavanaugh, M.P. (1995) Ion fluxes associated with excitatory amino acid transport. Neuron 15 721-728.

Zerangue, N. & Kavanaugh, M.P. (1996) Interaction of L-cysteine with a human excitatory amino acid transporter.Physiol 493 419-423.

Klamo, E.M., Drew, M.E., Landfear, S.M., & Kavanaugh, M.P. (1996) Kinetics and stoichiometry of a proton/myo-inositol cotransporter.Biol Chem 271 14937-14943.

Kavanaugh, M.P. & Kabat, D. (1996) Identification and characterization of a widely expressed phosphate transporter/retrovirus receptor family. Kidney Int 49 959-963.

Zerangue, N. & Kavanaugh, M.P. (1996) ASCT-1 is a neutral amino acid exchanger with chloride channel activity.Biol Chem 271 27991-27994.

Zerangue, N. & Kavanaugh, M.P. (1996) Flux coupling in a neuronal glutamate transporter. Nature 383 634-637

Kavanaugh, M.P., Bendahan, A., Zerangue, N., Zhang, Y., & Kanner, B.I. (1997) Mutation of a residue influencing potassium coupling in the glutamate transporter GLT-1 induces obligate exchange.Biol Chem 272 1703-1708.

Otis, T., Kavanaugh, M.P., & Jahr, C.E. (1997) Postsynaptic glutamate uptake at the climbing fiber-Purkinje cell synapse. Science 277 1515-1518.

Wadiche, J. I. & Kavanaugh, M. P. (1998) Macroscopic and microscopic properties of a cloned glutamate transporter/chloride channelNeurosci 18 7650-61

Eliasof, S., Arriza, J. L., Leighton, B. H., Amara, S. G. & Kavanaugh, M. P. (1998) Localization and function of five glutamate transporters cloned from the salamander retina. Vision Res 38 1443-5

Tzingounis, A. V., Lin, C. L., Rothstein, J. D. & Kavanaugh, M. P. (1998) Arachidonic acid activates a proton current in the rat glutamate transporter EAAT4 J Biol Chem 273 17315-7.

Cha, A., Zerangue, N., Kavanaugh, M.P., and Bezanilla, F. (1998) Fluorescence measurements of ion transport processes in Xenopus oocytes. Methods in Enzymology 296 566-577

Kavanaugh, M. P. (1998) Neurotransmitter transport: models in fluxProc Natl Acad Sci U S A 95, 12737-8.

Otis, T.S., and Kavanaugh, M.P. (2000) Isolation of current components and partial reaction cycles in the glial glutamate transporter EAAT2.Neurosci 20 2749-57.

Bendahan, A., Armon, A., Madani, N., Kavanaugh, M.P., and Kanner B.I. (2000) Arginine 447 plays a pivotal role in substrate interactions in a neuronal glutamate transporter.Biol Chem 275 37436-42.

Chaudhry FA, Krizaj D, Larsson P, Reimer RJ, Wreden C, Storm-Mathisen J, Copenhagen D, Kavanaugh M, Edwards RH. (2001) Coupled and uncoupled proton movement by amino acid transport system N. EMBO J 20: 7041-51.

Chaudhry F.A., Schmitz D, Reimer R.J., Larsson P, Gray A.T., Nicoll R, Kavanaugh M.P., Edwards R.H. Glutamine uptake by neurons: interaction of H+ with system A transporters. J Neurosci. 22 62-72 2002.

Stein, A., Vaseduvan, G. Carter, N.S., Ullman, B., Landfear, S.M., and Kavanaugh, M.P. (2003) Equilibrative nucleoside transporter family members from Leishmania donovani are electrogenic proton symporters. J. BiolChem. 278 35127-34.

Larsson, H.P., Tzingounis, A.V., Koch, H.P., and Kavanaugh, M.P. (2004) Fluorometric measurements of conformational changes in glutamate transporters. Proc. Nat. AcadSci.,101:3951-56.

Kavanaugh, MP (2004) Accessing a transporter structure. Nature 431:752-3.

Esslinger, CS Agarwal, S, et al., Kavanaugh, MP, and Bridges, RJ. (2005) “The Substituted Aspartate Analogue L-β-threo-Benzyl-Aspartate preferentially inhibits the neuronal excitatory amino acid transporter EAAT3.” Neuropharm. 850-861.

Leary GP, Stone EF, Holley DC, Kavanaugh MP. (2007) The glutamate and chloride permeation pathways are colocalized in individual neuronal glutamate transporter subunits.Neurosci 11:2938-42.

Holley, DC, and Kavanaugh, MP (2009) Interactions of alkali cations with glutamate transporters. Phil. Trans. Roy. Soc. 364(1514):155-61.

Kavanaugh, M.P. (2009) Glial Glutamate Transporters: Electrophysiology. In: Squire LR (ed.) Encyclopedia of Neuroscience, volume 4, pp. 805-809. Oxford: Academic Press.

Sun W, Hoffman KM, Holley DC, Kavanaugh MP. (2011) Specificity and actions of an arylaspartate inhibitor of glutamate transport at the Schaffer collateral-CA1 pyramidal cell synapse.PLoS One. 6(8):e23765.

Leary GP, Holley DC, Stone EF, Lyda BR, Kalachev LV, Kavanaugh MP. (2011)The central cavity in trimeric glutamate transporters restricts ligand diffusion.Proc Natl Acad Sci U S A. 108(36):14980-5.

Leary GP, Allen JE, Bunger PL, Luginbill JB, Linn CE Jr, Macallister IE, Kavanaugh MP, Wanner KW.(2012) Single mutation to a sex pheromone receptor provides adaptive specificity between closely related moth species.Proc Natl Acad Sci U S 109(35):14081-6.

Rau TF, Lu Q, Sharma S, Sun X, Leary G, Beckman ML, Hou Y, Wainwright MS, Kavanaugh M, Poulsen DJ, Black SM. (2012) Oxygen glucose deprivation in rat hippocampal slice cultures results in alterations in carnitine homeostasis and mitochondrial dysfunction.PLoS One. 7(9):e40881.

Stone E, Hoffman K, Kavanaugh M. (2012) Identifying neurotransmitter spill-over in hippocampal field recordings.Math Biosci. 240(2):169-86.

Calderón-Garcidueñas L, Mora-Tiscareño A, Styner M, Gómez-Garza G, Zhu H, Torres-Jardón R, Carlos E, Solorio-López E, Medina-Cortina H, Kavanaugh M, D'Angiulli A. (2012) White matter hyperintensities, systemic inflammation, brain growth, and cognitive functions in children exposed to air pollution.J Alzheimers Dis. 31(1):183-91.

Calderón-Garcidueñas L, Serrano-Sierra A, Torres-Jardón R, Zhu H, Yuan Y, Smith D, Delgado-Chávez R, Cross JV, Medina-Cortina H, Kavanaugh M, Guilarte TR. (2012) The impact of environmental metals in young urbanites' brains.Exp Toxicol Pathol. [Epub ahead of print]

Calderón-Garcidueñas L, Kavanaugh M, Block M, D'Angiulli A, Delgado-Chávez R, Torres-Jardón R, González-Maciel A, Reynoso-Robles R, Osnaya N, Villarreal-Calderon R, Guo R, Hua Z, Zhu H, Perry G, Diaz P. (2012) Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults. J Alzheimers Dis. 28(1):93-107.



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