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dc.contributor.authorJoshi, Prasad Ramesh
dc.date.accessioned2018-07-11T01:04:08Z
dc.date.available2018-07-11T01:04:08Z
dc.date.issued2005
dc.identifier.urihttp://hdl.handle.net/11122/8779
dc.descriptionThesis (Ph.D.) University of Alaska Fairbanks, 2005
dc.description.abstractThe serotonin type-3 receptor (5-HT3R) is widely distributed in peripheral and central nervous systems. This pentameric protein is a member of the Cys-loop superfamily of ligand gated ion channels and plays a role in mediating physiological processes in nervous, cardiovascular, and digestive systems. The ligand-binding domain of this receptor is extracellularly located and is composed of multiple putative loop structures. Based on structural and sequence homology with other members of the superfamily, it has been proposed that at least six such loops (loops A to F) contribute to the ligand-binding domain. Binding of agonist initiates a conformational change which is transduced to the channel, leading to channel opening (gating). The aim of this study was to elucidate the contribution of residues in loops B and E to the mechanism of channel gating in the 5-HT3R. To this end, the three critical tyrosine residues in the loop E region were characterized employing site-directed mutagenesis, electrophysiological studies as well as radio-ligand binding assays involving two structural classes of 5-HT3R agonists. In addition, structure/function analysis of the loop B region was carried out alanine-scanning mutagenesis. Experimental data were correlated with molecular modeling studies. These studies show that the hydroxytryptamine and phenylbiguanide class of compounds utilize different mechanisms of ligand binding and gating in the 5-HT3R. Studies involving the loop B reveal that this region plays a critical role in ligand binding and channel gating. Data obtained from comparison of ground state and agonist-bound models of the 5-HT 3R was correlated with biochemical data. Taken together, these data suggest that agonist interaction with loop B region probably initiates a conformational wave that results in intra- and inter- subunit hydrogen bonding interactions. Our data suggest that these interactions play a critical role in agonist-induced channel opening.
dc.subjectBiochemistry
dc.subjectNeurosciences
dc.titleStructure-Function Studies Of The Serotonin Type -3 Receptor Ligand -Binding Domain
dc.typeThesis
dc.type.degreephd
dc.contributor.chairSchulte, M. K.
refterms.dateFOA2020-03-05T16:18:21Z


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