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1. Chiu, Yi-Ting. STUDIES ON NEURITE OUTGROWTH AND RECEPTOR PHOSPHORYLATION FOLLOWING KAPPA OPIOID RECEPTOR ACTIVATION.
Degree: PhD, 2016, Temple University
Kappa opioid receptor (KOPR) is involved in many physiological functions and pharmacological responses such as analgesia, anti-pruritic effect, sedation, motor incoordination and aversion (Simonin et al., 1998; Liu-Chen, 2004). The cellular mechanisms following activation of KOPR involve in part Gi/o protein-dependent pathways (Law et al., 2000). Following KOPR activation, the receptor is phosphorylated and arrestins are recruited. Arrestins mediate agonist-dependent KOPR desensitization, internalization and down-regulation (Liu-Chen, 2004). In recent years, arrestins were found to initiate arrestin-dependent downstream signaling. Thus, agonist-promoted KOPR phosphorylation plays a pivotal role in KOPR regulation and signaling. Previous studies from our lab showed that in Chinese hamster ovary (CHO) cells stably transfected with the human KOPR (hKOPR), U50,488H induced phosphorylation (Li et al., 2002a); however, sites of phosphorylation were not determined. Using LC-MS/MS, our lab recently identified four residues (S356, T357, T363 and S369) to be the sites of U50,488H-promoted phosphorylation in the mouse KOPR (mKOPR) stably expressed in N2A cells (Chen et al., 2016). Antibodies were generated against phosphopeptides and purified and three antibodies were found to have high specificity for the mKOPR phosphorylated at S356/T357, T363 and S369, respectively (Chen et al., 2016). Our lab previously showed that while U50,488H promoted robust hKOPR phosphorylation and internalization, etorphine induced little phosphorylation and internalization, although both were potent full agonists in enhancing [35S]GTPγS (Li et al., 2002a; Zhang et al., 2002; Li et al., 2003). Etorphine caused lower levels of KOPR phosphorylation at all the four residues than U50,488H by immunoblotting with the phospho-specific antibodies (Chen et al., 2016). Using the SILAC (stable isotope labeling by amino acids in cell culture) approach, we have found that compared to etorphine, U50,488H promoted higher levels of single phosphorylation at T363 and S369 and double phosphorylation at T363+S369 and T357+S369 as well as triple phosphorylation at S356+T357+S369 (Chen et al., 2016). These results indicate that an above-threshold phosphorylation is required for KOPR internalization. It has been reported that KOPR is involved in neuronal differentiation and neurogenesis. In the first chapter, I focused on whether there are differences in the mechanisms underlying neurite outgrowth induced by U50,488H and etorphine. In the chapter 2, mechanisms of KOPR phosphorylation were characterized in detail using phospho-specific KOPR antibodies. Protein kinase C was found, for the first time, to be involved in agonist-promoted KOPR phosphorylation. The roles of PKC in behavioral effects induced by KOPR agonists in mice were examined. For the chapter 1, in Neuro2a mouse neuroblastoma cells stably transfected with the hKOPR (N2A-3HA-hKOPR), U50,488H robustly induced neurite outgrowth, but etorphine caused outgrowth to a much lower extent. G…Advisors/Committee Members: Liu-Chen, Lee-Yuan;, Ashby, Barrie, Unterwald, Ellen M., Abood, Mary Ellen, Tilley, Douglas G., Benovic, Jeffrey L.;.
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APA (6th Edition):
Chiu, Y. (2016). STUDIES ON NEURITE OUTGROWTH AND RECEPTOR PHOSPHORYLATION FOLLOWING KAPPA OPIOID RECEPTOR ACTIVATION. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,384383
Chicago Manual of Style (16th Edition):
Chiu, Yi-Ting. “STUDIES ON NEURITE OUTGROWTH AND RECEPTOR PHOSPHORYLATION FOLLOWING KAPPA OPIOID RECEPTOR ACTIVATION.” 2016. Doctoral Dissertation, Temple University. Accessed October 26, 2020. http://digital.library.temple.edu/u?/p245801coll10,384383.
MLA Handbook (7th Edition):
Chiu, Yi-Ting. “STUDIES ON NEURITE OUTGROWTH AND RECEPTOR PHOSPHORYLATION FOLLOWING KAPPA OPIOID RECEPTOR ACTIVATION.” 2016. Web. 26 Oct 2020.
Chiu Y. STUDIES ON NEURITE OUTGROWTH AND RECEPTOR PHOSPHORYLATION FOLLOWING KAPPA OPIOID RECEPTOR ACTIVATION. [Internet] [Doctoral dissertation]. Temple University; 2016. [cited 2020 Oct 26]. Available from: http://digital.library.temple.edu/u?/p245801coll10,384383.
Council of Science Editors:
Chiu Y. STUDIES ON NEURITE OUTGROWTH AND RECEPTOR PHOSPHORYLATION FOLLOWING KAPPA OPIOID RECEPTOR ACTIVATION. [Doctoral Dissertation]. Temple University; 2016. Available from: http://digital.library.temple.edu/u?/p245801coll10,384383