David Bredt, MD/PhD
Molecular Basis of Postsynaptic Organization

email bredt@phy.ucsf.edu phone 415-476-6310 415-476-6734 office location physical address: N-272F, Genentech Hall 600 16th Street Mission Bay Campus mailing address: UCSF Genentech Hall 600 16th Street Box 2140 San Francisco, CA 94143-2140 For internal campus mail: Box 2140 other websites PIBS website Biomedical Sciences Graduate Program Research Summary | Current Projects Lab Personnel | Publications

Neurons take in vast amounts of chemical information at their postsynaptic termini, and a central question is how this complex array of inputs is correctly processed. Our lab focuses on postsynaptic processing at excitatory synapses in brain. Transmission at these excitatory synapses is mediated primarily by glutamate acting on two classes of ligand gated ion channels: AMPA receptors and NMDA receptors. The AMPA receptors are involved in moment-to-moment signaling, whereas NMDA receptors play an important role in initiating synaptic plasticity. A key breakthrough in understanding mechanisms for synapse assembly came from the discovery that proteins containing PDZ motifs play central roles in scaffolding receptors and signaling elements. The prototypical PDZ protein, PSD-95, associates with NMDA receptors and a downstream effector neuronal nitric oxide synthase. By bridging the NMDA receptor to nNOS, PSD-95 functions as a scaffold to enhance activation of calmodulin-dependent nNOS activity by Ca2+ influx through the NMDA receptor. In addition to mediating synapse assembly through its PDZ domains, PSD-95 participates in synaptic plasticity through its regulatory domains. We are using cellular, structural and physiological approaches to understand how the regulatory domains of PSD-95, which include an SH3 domain, a guanylate kinase domain, and sites for N-terminal palmitoylation mediate synaptic plasticity. Whereas numerous cytoskeletal elements bind to glutamate receptors, the first transmembrane protein found to interact with glutamate receptors is stargazin. Working together with Dr. Roger Nicoll's group, we found that stargazer mutant mice lack synaptic AMPA responses due to a block in AMPA receptor trafficking. Stargazin is a tetraspanin, a protein with four transmembrane domains that links AMPA receptors to PDZ proteins at the synapse. Our current work focuses on how stargazin promotes delivery of AMPA receptors to the plasma membrane and on how stargazin regulates the synaptic cycling of AMPA receptors that underlies synaptic plasticity. See above. Only current lab members are listed below. Click on the icon to open a list of former lab members. Bonnie Firestein Postdoctoral Fellow 7/95-Present Ph.D. UC San Diego Nitric oxide and neuronal development Karen Christopherson Graduate Student 9/95-Present B.S. UC Berkeley NOS/NMDAR protein complex Sarah Craven Graduate Student 9/96-Present B.A. Boston University PSD-95 localization Aaron McGee Graduate Student 9/96-Present B.A. Univ. of Colorado Cellular mechs of synaptic plasticity Kiwon Jo Postdoctoral Fellow 8/97-Present Ph.D. Univ. of North Carolina FSH muscular dystrophy Alaa El-Din El Husseini Postdoctoral Fellow 8/97-Present Ph.D. Univ. of British Columbia, Vancouver Mechanisms for postsynaptic targeting Hidemi Misawa Postdoctoral Fellow 4/98-Present Ph.D. Kyoto University Postsynaptic organization Srikanth Dakoji Postdoctoral Fellow 11/98-Present Ph.D. Univ. of Minnesota Palmitoylation and protein targeting Dane Chetkovich Postdoctoral Fellow 11/98-Present M.D., Ph.D. Baylor College of Medicine Postsynaptic development Robert Bunn Postdoctoral Fellow 2/1/99-Present Ph.D. Louisiana State Univ. ALP & muscular dystrophy Only selected publications are listed below. Click on the icon to open a complete list of publications. Craven-S-E. Alaa E. El-Husseini-A-E. and Bredt-D-S. Synaptic targeting of the postsynaptic density protein PSD-95 mediated by lipid and protein motifs Neuron 1999 22: 497-509. Hillier-B-J. Christopherson-K-S. Prehoda-K-E. Bredt-D-S. and Lim-W-A. Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin complex Science 1999 284: 812-815. El-Husseini-A-E. Craven-S.E. Chetkovich-D-M. Firestein-B.L. Schnell-E. Aoki-C. and Bredt-D-S. Dual palmitoylation of PSD-95 mediates its vesiculotubular sorting, postsynaptic targeting and ion channel clustering. Journal of Cell Biology 2000 148: 159-171. El-Husseini-A-E. Schnell-E. Chetkovich-D-M. Nicoll-R-A. and Bredt-D-S. PSD-95 Drives Maturation of Excitatory Synapses Science 2000 290: 1364-1368. Chen-L. Chetkovich-D-M. Petralia-R-S. Sweeney-N. Kawaski-Y. Wenthold-R-J. Bredt-D-S. and Nicoll-R-A. Stargazin regulates the synaptic targeting of AMPA receptors by two distinct mechanisms Nature 2000 408: 936-943 .