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dc.contributor.authorDeng, Hong Bing
dc.date.accessioned2012-04-04T12:07:55Z
dc.date.available2012-04-04T12:07:55Z
dc.date.issued1999
dc.identifier.urihttp://hdl.handle.net/10713/1226
dc.descriptionUniversity of Maryland, Baltimore. Pharmaceutical Sciences. Ph.D. 1999en_US
dc.description.abstractA prominent characteristic of opioid drugs is their ability to induce tolerance and dependence in human. The mu receptor phosphorylation and desensitization are important cellular mechanisms that may contribute to these neuroadaptive processes. The overall goal of the present research is to understand the molecular mechanisms of mu opioid receptor phosphorylation and desensitization as well as study the molecular structure of mu opioid receptor. We employed molecular biology and cell biology techniques combined with pharmacological methods to accomplish these research goals in three aspects. In the first part, we characterized agonist-induced mu opioid receptor phosphorylation events in brain tissues. We found that in the thalamus of morphine-tolerant rats, both the basal and agonist stimulated receptor phosphorylation levels were enhanced compared with those observed in normal rats. The enhanced phosphorylation level correlated well with the desensitization of their cellular response. These findings demonstrate that agonist induced mu opioid receptor phosphorylation Plays an important role in receptor desensitization, which may contribute to the mechanisms underlying tolerance and dependence. In the second part, we determined the role of the C-terminus in mu opioid receptor phosphorylation and desensitization by C-terminal deletion and point mutation of the receptor. Our data suggest that the C-terminus is an important domain involved in the 4 opioid receptor phosphorylation and desensitization. We further found that threonine 394 is a crucial residue that is required for agonist-induced mu opioid receptor phosphorylation and desensitization. In the last part, we investigated the effects of sulfhydryl reagents on mu receptor binding and identified that the cysteine residues in TMIII (C161), TMIV (C192), TMV (C237) and TMVII (C332) of the receptor that are critical cysteines responsible for the sensitivity of mu opioid receptor binding to sulfhydryl specific reagents. These four cysteines may be located in or near the receptor binding site. These findings provide important information for understanding the molecular mechanisms of interaction between the mu opioid receptor and its ligands.en_US
dc.language.isoen_USen_US
dc.subjectBiology, Neuroscienceen_US
dc.subjectBiophysics, Generalen_US
dc.titleThe in vitro and in vivo studies of the structure and functional regulation of the mu-opioid receptoren_US
dc.typedissertationen_US
dc.contributor.advisorWang, Jia Bei
dc.identifier.ispublishedYes
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