Activation of guanine nucleotide binding proteins by opioid receptors.
dc.contributor.author | Alt, Andrew Jason | |
dc.contributor.advisor | Woods, James H. | |
dc.date.accessioned | 2016-08-30T18:10:39Z | |
dc.date.available | 2016-08-30T18:10:39Z | |
dc.date.issued | 2000 | |
dc.identifier.uri | http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqm&rft_dat=xri:pqdiss:9990840 | |
dc.identifier.uri | https://hdl.handle.net/2027.42/132728 | |
dc.description.abstract | Opioid receptors are coupled to heterotrimeric guanine nucleotide binding proteins (G proteins). Agonist binding to opioid receptors leads to the activation of G proteins, which in turn mediate the intracellular effects of opioid drugs. While a great deal is known about the interactions between receptors and G proteins, some fundamental questions remain unanswered. For instance, it remains unclear whether opioid receptors have access to the cell's entire pool of G proteins, or if G proteins are allocated to specific receptors. Also, although opiates are among the best characterized drugs, relatively little is known about the peptides which act at these receptors endogenously and how the actions of these ligands compare to those of the classical opiates such as morphine. The ability of endogenous opioids to activate mu opioid receptors was examined. Most endogenous opioids were full agonists at the mu receptor. Interestingly, the only exceptions were the newly discovered endomorphins, which have been postulated to be the endogenous mu ligands. The primary purpose of this research was to determine whether opioid receptors share individual G proteins. This was tested in two ways. First, in cells expressing mu receptors, receptor concentration was reduced using an alkylating agent, and the effect on maximal G protein activation was measured. It was found that for each receptor that was inactivated, a commensurate number of G proteins were lost, implying that each mu receptor accesses only its own G proteins. Second, the ability of mu and delta opioid receptor types to interact with the same individual G proteins was measured, using the ability of receptor activation to stimulate both the association and the dissociation of guanosine-5<super>'</super>-O-(3-[<super>35</super>S]thio)thiphosphate ([<super>35</super>S]GTPgammaS) from G proteins. It was found that [<super> 35</super>S]GTPgammaS which was bound to G proteins as a result of mu receptor activation could be dissociated by delta receptor activation, and vice versa. These results demonstrate that mu and delta receptors can share individual G proteins. The results of this research show a general lack of selectivity in the opioid system at the cellular level, both in terms of receptor activation by endogenous ligands, and G protein activation by receptors. | |
dc.format.extent | 148 p. | |
dc.language | English | |
dc.language.iso | EN | |
dc.subject | Activation | |
dc.subject | Endogenous Opioids | |
dc.subject | Guanine | |
dc.subject | Nucleotide Binding Proteins | |
dc.subject | Opioid Receptors | |
dc.title | Activation of guanine nucleotide binding proteins by opioid receptors. | |
dc.type | Thesis | |
dc.description.thesisdegreename | PhD | en_US |
dc.description.thesisdegreediscipline | Health and Environmental Sciences | |
dc.description.thesisdegreediscipline | Pharmacology | |
dc.description.thesisdegreegrantor | University of Michigan, Horace H. Rackham School of Graduate Studies | |
dc.description.bitstreamurl | http://deepblue.lib.umich.edu/bitstream/2027.42/132728/2/9990840.pdf | |
dc.owningcollname | Dissertations and Theses (Ph.D. and Master's) |
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