Neurotransmitter-gated ion channels mediate synaptic transmission throughout the nervous system. The nicotinic acetylcholine receptor (AChR) from skeletal muscle has served as a prototype for understanding the members of the superfamily of receptors, which includes neuronal nicotinic, glycine, GABAA, and 5-HT3 receptors. The essential function of this class of proteins is to transduce neurotransmitter binding into opening of an intrinsic ion channel. To better understand how neurotransmitter-gated ion channels function, the work proposed in this application will identify amino acids in transmembrane domains of the AChR that govern rates of opening and closing of the channel. The approach combines site-directed mutagenesis of residues in transmembrane domains and expression in mammalian cells with single channel recording and kinetic analysis. The overall findings will relate transmembrane domain structure to elementary steps underlying gating of the AChR channel.

Agency
National Institute of Health (NIH)
Institute
Fogarty International Center (FIC)
Type
Small Research Grants (R03)
Project #
1R03TW001185-01
Application #
2908322
Study Section
International and Cooperative Projects 1 Study Section (ICP)
Program Officer
Michels, Kathleen M
Project Start
1999-09-30
Project End
2002-09-29
Budget Start
1999-09-30
Budget End
2000-09-29
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
City
Rochester
State
MN
Country
United States
Zip Code
55905
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Bouzat, Cecilia; Gumilar, Fernanda; del Carmen Esandi, Maria et al. (2002) Subunit-selective contribution to channel gating of the M4 domain of the nicotinic receptor. Biophys J 82:1920-9
De Rosa, Maria Jose; Rayes, Diego; Spitzmaul, Guillermo et al. (2002) Nicotinic receptor M3 transmembrane domain: position 8' contributes to channel gating. Mol Pharmacol 62:406-14
Rayes, D; De Rosa, M J; Spitzmaul, G et al. (2001) The anthelmintic pyrantel acts as a low efficacious agonist and an open-channel blocker of mammalian acetylcholine receptors. Neuropharmacology 41:238-45
Spitzmaul, G; Dilger, J P; Bouzat, C (2001) The noncompetitive inhibitor quinacrine modifies the desensitization kinetics of muscle acetylcholine receptors. Mol Pharmacol 60:235-43
Bouzat, C; Barrantes, F; Sine, S (2000) Nicotinic receptor fourth transmembrane domain: hydrogen bonding by conserved threonine contributes to channel gating kinetics. J Gen Physiol 115:663-72