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richard.bridges

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Name: Richard Bridges

Title: Regents Professor & Chair

Email: richard.bridges@umontana.edu

Phone: 406-243-4972

Office: SB 395B

Lab Phone: 406-243-4308

Lab: SB 376

 

Background

After completing undergraduate work in Biochemistry at the University of California at Davis, Richard Bridges received a Ph.D. in Biochemistry from Cornell Medical College in 1984. Following postdoctoral and faculty positions at the University of California at Irvine, he moved to The University of Montana as an Associate Professor in 1993. He was promoted to Professor in 1998.

 

Research Statement

Research in the Bridges laboratory focuses on the transport systems responsible for mediating the uptake and sequestration of the excitatory neurotransmitter glutamate. Using conformationally constrained analogues of this acidic amino acid, Bridges and his associates probe the pharmacological specificity and the physiologically roles of these transporters in the brain and spinal cord. This work employs a wide range of experimental systems (e.g., subcellular preparations, primary tissue culture, cell lines expressing cloned transporters) and approaches (e.g., molecular modeling, organic synthesis, radiotracer flux, HPLC, radioligand autoradiography).

Elucidating how the levels of this excitatory neurotransmitter are regulated in the central nervous system is critical to understanding both glutamate-mediated neuronal signaling and glutamate-mediated neuropathology. Cellular transporters rapidly translocate extracellular glutamate into neurons and glia, potentially contributing to signal termination, the recycling of the neurotransmitter, and the maintenance of sub-pathological levels of glutamate. Another glutamate transporter, distinct from the cellular system, is present on synaptic vesicles and serves to concentrate glutamate in these vesicles prior to its release during excitatory neurotransmission.

Work in the laboratory has led to the discovery of several potent and specific inhibitors of the cellular glutamate transporters. In addition to their utility in modeling the binding sites on these proteins, these compounds have been exploited in a number of physiological preparations to investigate the consequences of impaired function. Further, considerable progress has been made in developing compounds that differentiate the processes of binding and translocation, as well exhibit selectivity among the different subclasses of cellular transporters. Recent progress has also been made in identifying a number of new inhibitors of the glutamate transporter present on synaptic vesicles. As few inhibitors have been identified for this uptake system, these compounds should be particularly valuable in investigating mechanisms underlying glutamate-mediated neurotransmission.

Other research in the group involves using conformationally constrained glutamate analogues as probes of the excitatory amino acid receptors and receptor-mediated neuronal pathology. The Bridges lab also maintains active collaborations with research groups at a number of universities including the University of California at Irvine, King's College London, and the Vollum Institute at the Oregon Health Science University.

 

Publications

Etoga, J.G., Ahmed, S.K., Patel, S,. Bridges, R.J., and Thompson, C.M. (2010) Conformationally-Restricted Amino Acid Analogues Bearing a Distal Sulfonic Acid Show Selective Inhibition of System Xc- over the Vesicular Glutamate Transporter Bioorganic & Medicinal Chemistry Letters, 20 (18), 2680-2683.

Patel, S., Rajale, T., O’Brien, E., Burkjart, D., Nelson, J., Twamley, B., Blumenfeld, A.,Szabon-Watol, M., Gerdes, J., Bridges, R., Natale, N. (2010) Isoxazole analogues bind the System xc_ transporter: Structure–activityrelationship and pharmacophore modelBioorganic & Medicinal Chemistry, 18, 202-213. (NIHMS158080)

Natale N.R., Szabon-Watola, M.I., Twamley, B., Bridges, R.J., Patel,S., and Rajale, T. (2009) Ethyl 4-{1-[(2,4-Dinitro-phenyl)-hydrazono]-ethyl}-5-(naphthalen-2-ylmethoxymethyl)-isoxazole-3-carboxylate”, Acta Cryst., E65, 144-145.

Bridges, R.J. and Patel, S.A.(2009) Pharmacology of Glutamate Transport in the CNS: Substrates and Inhibitors of Excitatory Amino Acid Transporters (EAATs) and the Glutamate/Cystine Exchanger System xc-; in Topics in Medicinal Chemistry: Transporters as Targets for Drugs, (S. Napier, M. Bingham ed.) Springer; NY,NY; pp 187-222.

Mavencamp, T., Rhoderick, J.F., Bridges, R.J., and Esslinger, C.S. (2008) Stereoselective synthesis and preliminary pharmacological evaluation of novel derivatives of L-β threo-benzyl aspartate as inhibitors of the neuronal glutamate transporter EAAT-3. Bioorganic & Medicinal Chemistry Letters, 16, 7740-7748.

Queen, SA, Kesslak, JP and Bridges, R.J. (2007) Regional distribution of sodium-dependent excitatory amino acid transporters in rat spinal cord. Journal of Spinal Cord Medicine, 30, 263-71.

Esslinger CS, Agarwal S, Gerdes J, Wilson PA, Davis ES, Awes AN, O'Brien E, Mavencamp T, Koch HP, Poulsen DJ, Rhoderick JF, Chamberlin AR, Kavanaugh MP, Bridges RJ. (2005) The substituted aspartate analogue L-b-threo-benzyl-aspartate preferentially inhibits the neuronal excitatory amino acid transporter EAAT3. Neuropharmacology , 49, 850-861

Thompson, C.M., Davis, E., Carrigan, C.N., Cox, H.D., Bridges, R.J., and Gerdes, J.M. (2005) Inhibitors of the glutamate vesicular transporter (VGLUT). Current Medicinal Chemistry, 12, 2041-2056.

Bridges, R.J. and Esslinger, C.S. (2005) The excitatory amino acid transporters: pharmacological insights on substrate and inhibitor specificity. Pharmacology and Therapeutics, 107, 271-285.

Warren, B.A., Patel, S.A., Nunn, P.B., and Bridges, R.J. (2004) The Lathyrus excitotoxin b-N-oxalyl-L-a,b-diaminopropionic acid (b-L-ODAP) is a substrate of the L-glutamate/L-cystine exchanger system Xc-: Toxicology and Applied Pharmacology, 200, 83-92.


The University of Montana-Missoula
The Department of Biomedical & Pharmaceutical Sciences
32 Campus Drive, Skaggs 395
Missoula, MT 59812-1552
Phone 406.243.4767 Fax: 406.243.5228
Email: biomed@umontana.edu

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