Abstract

This project focuses on the functional characteristics of molecules that render """"""""fast"""""""" synapses, exquisite electrochemical machines, specialized to function on a time scale of milliseconds and a distance scale of micrometers. 1. Functional studies will continue on the nicotinic receptor superfamily. Tethered agonists and cation-it interactions will be studied. Fluorescent probes of receptor conformation will be developed and studied. 2. Structure/function relations will be studied in the P2X receptor superfamily. The mechanism for the large pore that appears after sustained exposure to ATP will be explored. The disulfide topology of the extracellular region will be explored. Mechanisms will be studied for the functional interaction between P2X and nicotinic receptors. 3. The experiments will develop ways to count local densities Of synaptic proteins: transporters, starting with the mouse GABA transporter mGAT1; and receptors, starting with the nAChR alpha4 subunit and P2X2 subunit Ion channels and transporters, including but not limited to those involved in synaptic transmission, are important in many aspects of pathophysiology and therapeutics.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS011756-26A1
Application #
6197948
Study Section
Special Emphasis Panel (ZRG1-MDCN-3 (01))
Program Officer
Talley, Edmund M
Project Start
1977-12-01
Project End
2004-07-31
Budget Start
2000-08-05
Budget End
2001-07-31
Support Year
26
Fiscal Year
2000
Total Cost
$480,410
Indirect Cost

  Institution

Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125

  Publications

Blum, Angela P; Van Arnam, Ethan B; German, Laurel A et al. (2013) Binding interactions with the complementary subunit of nicotinic receptors. J Biol Chem 288:6991-7
Puskar, Nyssa L; Lester, Henry A; Dougherty, Dennis A (2012) Probing the effects of residues located outside the agonist binding site on drug-receptor selectivity in the nicotinic receptor. ACS Chem Biol 7:841-6
Srinivasan, Rahul; Richards, Christopher I; Xiao, Cheng et al. (2012) Pharmacological chaperoning of nicotinic acetylcholine receptors reduces the endoplasmic reticulum stress response. Mol Pharmacol 81:759-69
Richards, Christopher I; Luong, Khai; Srinivasan, Rahul et al. (2012) Live-cell imaging of single receptor composition using zero-mode waveguide nanostructures. Nano Lett 12:3690-4
Srinivasan, Rahul; Richards, Christopher I; Dilworth, Crystal et al. (2012) Förster resonance energy transfer (FRET) correlates of altered subunit stoichiometry in cys-loop receptors, exemplified by nicotinic ?4?2. Int J Mol Sci 13:10022-40
Tavares, Ximena Da Silva; Blum, Angela P; Nakamura, Darren T et al. (2012) Variations in binding among several agonists at two stoichiometries of the neuronal, ?4?2 nicotinic receptor. J Am Chem Soc 134:11474-80
Murray, Teresa A; Bertrand, Daniel; Papke, Roger L et al. (2012) ?7?2 nicotinic acetylcholine receptors assemble, function, and are activated primarily via their ?7-?7 interfaces. Mol Pharmacol 81:175-88
Shanata, Jai A P; Frazier, Shawnalea J; Lester, Henry A et al. (2012) Using mutant cycle analysis to elucidate long-range functional coupling in allosteric receptors. Methods Mol Biol 796:97-113
Puskar, Nyssa L; Xiu, Xinan; Lester, Henry A et al. (2011) Two neuronal nicotinic acetylcholine receptors, alpha4beta4 and alpha7, show differential agonist binding modes. J Biol Chem 286:14618-27
Pless, Stephan A; Hanek, Ariele P; Price, Kerry L et al. (2011) A cation-? interaction at a phenylalanine residue in the glycine receptor binding site is conserved for different agonists. Mol Pharmacol 79:742-8

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