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You searched for +publisher:"The Ohio State University" +contributor:("Bohn, Laura"). Showing records 1 – 3 of 3 total matches.

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The Ohio State University

1. Raehal, Kirsten Michele. Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice.

Degree: PhD, Integrated Biomedical Sciences, 2009, The Ohio State University

Opioid drugs are potent analgesics; however, they also produce several adverse side effects including constipation, antinociceptive tolerance, and physical dependence by activating the mu opioid receptor, a G protein-coupled receptor (GPCR). There is a substantial literature that suggests that the GPCR regulatory proteins G protein-coupled receptor kinases (GRKs) and beta-arrestins play a key role in regulating mu opioid receptor signaling and responsiveness. In vivo, the loss of beta-arrestin2 significantly alters morphine-induced analgesia, antinociceptive tolerance, respiratory suppression, and reward. Moreover, distinct opioid agonists have been shown to differ in their propensity to promote interactions between the mu opioid receptor and beta-arrestins and such agonist directed events may ultimately determine the functional response of the receptor to a particular drug. Therefore, we hypothesize that GRK and beta-arrestin2-mediated mu opioid receptor regulation may determine the extent of opioid-induced side effects including constipation, antinociceptive tolerance, and physical dependence, in a manner that is specifically influenced by different opioid agonists and cellular environments. Using mice genetically lacking individual GRKs and beta-arrestin2, we evaluated distinct opioid agonists (morphine, methadone, and fentanyl) for their ability to elicit constipation, antinociceptive tolerance, and physical dependence. We find that beta-arrestin2 is important in determining the expression of morphine-induced constipation, antinociceptive tolerance, and physical dependence, even more so than GRKs. However, while all responses evaluated in response to morphine were affected by the loss of beta-arrestin2, only methadone-induced physical dependence was altered in the beta-arrestin2-knockout mice, suggesting that beta-arrestin2 differentially affects these opioid-mediated responses in an agonist-dependent manner. Collectively, these results provide evidence that distinct opioid agonists can influence mu opioid receptor regulation and responsiveness and that the contribution of a particular regulatory factor to receptor function can differ based upon the specific cell composition and physiology assessed. Advisors/Committee Members: Bohn, Laura (Advisor).

Subjects/Keywords: Pharmacology; opioid; arrestin; G protein-coupled receptor kinase; gastrointestinal; physical dependence; tolerance

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Raehal, K. M. (2009). Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1236884585

Chicago Manual of Style (16th Edition):

Raehal, Kirsten Michele. “Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice.” 2009. Doctoral Dissertation, The Ohio State University. Accessed April 02, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1236884585.

MLA Handbook (7th Edition):

Raehal, Kirsten Michele. “Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice.” 2009. Web. 02 Apr 2020.

Vancouver:

Raehal KM. Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice. [Internet] [Doctoral dissertation]. The Ohio State University; 2009. [cited 2020 Apr 02]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1236884585.

Council of Science Editors:

Raehal KM. Opioid-Induced Side Effects in Beta-arrestin2 adn G Protein-Coupled Receptor Kinase Knockout Mice. [Doctoral Dissertation]. The Ohio State University; 2009. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1236884585


The Ohio State University

2. Schmid, Cullen L. Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2.

Degree: PhD, Neuroscience Graduate Studies Program, 2011, The Ohio State University

The G protein-coupled, serotonin 2A (5-HT2A) receptor is a major drug target for the treatment of a number of mental health disorders, including schizophrenia, anxiety and depression. In addition to modulating several of the physiological effects of the neurotransmitter serotonin, activation of the 5-HT2A receptor mediates the psychotomimetic effects of serotonergic hallucinogenic drugs, such as lysergic acid diethylamide (LSD), 2,5-dimethoxy-4-iodoamphetamine (DOI) and 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). Though hallucinogens are agonists at the 5-HT2A receptor, not all 5-HT2A receptor agonists induce hallucinations in humans, including the endogenous ligand serotonin. Therefore, the activation of the 5-HT2A receptor can result in different biological responses depending upon the chemical nature of the ligand, a concept that has been referred to as “functional selectivity.” One way in which ligands can induce differential signaling at GPCRs is through interactions with beta-arrestins, which can act to dampen or facilitate receptor signaling cascades or mediate the internalization of receptors into intracellular vesicles. The overarching hypothesis of this dissertation is that the interaction between the regulatory protein, beta-arrestin2, and the 5-HT2A receptor is a critical point in the divergence of agonist-directed 5-HT2A receptor responsiveness. Using mice lacking beta-arrestin2, we evaluate 5-HT2A receptor trafficking and signaling in vivo for serotonin, the hallucinogenic agonists DOI and 5-MeO-DMT and the endogenous, hallucinogenic metabolite of serotonin, N-methylserotonin. We find that beta-arrestin2 mediates 5-HT2A receptor trafficking in primary neuronal cultures and can facilitate 5-HT2A receptor-mediated signaling cascades in the mouse frontal cortex, although its role is entirely dependent upon the agonist acting at the receptor. Serotonin requires beta-arrestins to internalize the 5-HT2A receptor and to scaffold the signaling kinases Akt and Src to the receptor. The formation of this receptor scaffold results in an increase in Akt activity, which is disrupted in the absence of beta-arrestin2, while the reintroduction of beta-arrestin2 into primary cortical neurons rescues serotonin-induced phosphorylation of Akt. Moreover, the disruption of these cellular events, either by the absence of beta-arrestin2 or by inhibiting the kinases, results in the inability of serotonin to induce the head twitch response in mice, which is a behavioral model of 5-HT2A receptor activation in the mouse frontal cortex. In contrast, DOI maintains its ability to internalize the 5-HT2A receptor in the absence of beta-arrestin2 and DOI, 5-MeO-DMT and N-methylserotonin do not activate beta-arrestin2-mediated signaling cascades in mouse embryonic fibrobalsts, primary cortical neurons or the mouse frontal cortex. The activation of the head twitch response by these hallucinogenic agonists is not disrupted in beta-arrestin2-knockout mice or in the presence of inhibitors to Akt. Collectively, these studies advance our… Advisors/Committee Members: Bishop, Georgia (Advisor), Bohn, Laura (Advisor).

Subjects/Keywords: Neurosciences; Pharmacology; G protein-coupled receptor; Serotonin 2A receptor; beta-arrestin2; hallucinogens; functional selectivity

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Schmid, C. L. (2011). Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1300287547

Chicago Manual of Style (16th Edition):

Schmid, Cullen L. “Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2.” 2011. Doctoral Dissertation, The Ohio State University. Accessed April 02, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1300287547.

MLA Handbook (7th Edition):

Schmid, Cullen L. “Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2.” 2011. Web. 02 Apr 2020.

Vancouver:

Schmid CL. Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2. [Internet] [Doctoral dissertation]. The Ohio State University; 2011. [cited 2020 Apr 02]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1300287547.

Council of Science Editors:

Schmid CL. Differential regulation of serotonin 2A receptor responsiveness by agonist-directed interactions with beta-arrestin2. [Doctoral Dissertation]. The Ohio State University; 2011. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1300287547

3. Groer, Chad E. Agonist-selective regulation of the mu opioid receptor by ßarrestins.

Degree: PhD, Integrated Biomedical Science Graduate Program, 2010, The Ohio State University

Morphine and other opiates mediate their effects through activation of the mu opioid receptor (MOR). Activation of the MOR results in recruitment of regulatory proteins, ßarrestins, that can regulate how this receptor signals. In vivo studies suggest that disruption of ßarrestin-mediated MOR regulation may enhance opiate-induced antinociception and reduce tolerance and certain unwanted side effects. Therefore, by understanding the cellular mechanisms by which this receptor is regulated, the development of analgesics which preserve the beneficial effects of opiates while eliminating unwanted side effects may be possible. In this dissertation we test the hypothesis that MOR agonists can bias MOR-ßarrestin interactions, and that ßarrestin recruitment profiles, in turn, may determine cellular responses evoked by these agonists. In the first data portion of this dissertation, we characterize several novel MOR agonists that are unable to promote ßarrestin recruitment. Herkinorin is a moderately selective agonist at the MOR, based on the structure of a natural product, Salvinorin A. We find that herkinorin promotes very little MOR phosphorylation, does not recruit ßarrestins, and does not induce receptor internalization in transfected cells. Herkinorin is unable to induce ßarrestin recruitment or MOR internalization under conditions that facilitate receptor phosphorylation and subsequent ßarrestin recruitment with other agonists. We also evaluated several derivatives of herkinorin with similar ßarrestin recruitment and MOR internalization profiles. Therefore, herkinorin and its derivatives may be a promising step toward recapitulating morphine’s effects in ßarr2-KO mice, which have been used to demonstrate that MOR activation without recruiting ßarrestin2 may be therapeutically useful, by producing analgesia with reduced side effects. In the second data portion of this dissertation, we evaluate the interaction and functional consequences of MOR regulation by ßarrestin1 and ßarrestin2, in response to the classical agonists, DAMGO and morphine. Using both qualitative (microscopy) and quantitative (cell surface biotinylation and BRET) approaches, we have confirmed that DAMGO can induce robust interactions between the MOR and both ßarrestins. Morphine, however, selectively promotes interactions with ßarrestin2. Additionally, the agonist specific ßarrestin interactions are required for internalization of the MOR. Finally, we show that ßarrestin1 is required for agonist-induced MOR ubiquitination, such that only DAMGO, and not morphine, is able to promote MOR ubiquitination. Taken together, these data suggest that MOR regulation is highly dependent on the complement of proteins available to interact with the MOR, and that the nature of the ligand can determine how the MOR is regulated by the available proteins. Therefore, the development of biased ligands for the MOR should focus activation of the MOR, but circumventing ßarrestin-mediated regulation. These concepts may be critical to consider in the… Advisors/Committee Members: Sadee, Wolfgang (Committee Chair), Bohn, Laura (Advisor).

Subjects/Keywords: Pharmacology; opioid arrestin herkinorin morphine

…Integrated Biomedical Science Graduate Program College of Medicine The Ohio State University… …Ohio State University Columbus, OH June 2004. …...... . . . . . .. . .. . B.S. in… …Ohio State University Columbus, OH June 2004-Present …... . .. ….Ph.D. Candidate… …Undergraduate Research Assistant Dept. of Molecular and Cellular Biochemistry College of Medicine The… …Pharmaceutical Sciences Magna Cum Laude, Graduated with Distinction and Honors College of Pharmacy The… 

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Record DetailsSimilar RecordsGoogle PlusoneFacebookTwitterCiteULikeMendeleyreddit

APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Groer, C. E. (2010). Agonist-selective regulation of the mu opioid receptor by ßarrestins. (Doctoral Dissertation). The Ohio State University. Retrieved from http://rave.ohiolink.edu/etdc/view?acc_num=osu1284396146

Chicago Manual of Style (16th Edition):

Groer, Chad E. “Agonist-selective regulation of the mu opioid receptor by ßarrestins.” 2010. Doctoral Dissertation, The Ohio State University. Accessed April 02, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1284396146.

MLA Handbook (7th Edition):

Groer, Chad E. “Agonist-selective regulation of the mu opioid receptor by ßarrestins.” 2010. Web. 02 Apr 2020.

Vancouver:

Groer CE. Agonist-selective regulation of the mu opioid receptor by ßarrestins. [Internet] [Doctoral dissertation]. The Ohio State University; 2010. [cited 2020 Apr 02]. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1284396146.

Council of Science Editors:

Groer CE. Agonist-selective regulation of the mu opioid receptor by ßarrestins. [Doctoral Dissertation]. The Ohio State University; 2010. Available from: http://rave.ohiolink.edu/etdc/view?acc_num=osu1284396146

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