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    Characterization of SUMOylation of 5-HT1ARs

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    Sugandha_ku_0099M_16699_DATA_1.pdf (781.1Kb)
    Issue Date
    2019-08-31
    Author
    Sugandha, -
    Publisher
    University of Kansas
    Format
    47 pages
    Type
    Thesis
    Degree Level
    M.S.
    Discipline
    Pharmacology & Toxicology
    Rights
    Copyright held by the author.
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    Abstract
    Serotonin 1A receptors (5-HT1AR) are G-protein coupled receptors involved in the control of mood, cognition and memory. Clinical and animal studies have demonstrated that abnormal levels of 5-HT1AR lead to anxiety-like and depressive-like phenotypes. Previous studies in our lab have shown that 5-HT1AR can undergo SUMOylation, a post-translational modification process analogous to ubiquitylation but involving conjugation of small ubiquitin-like modifiers (SUMOs). SUMOylated 5-HT1AR is located in the cell membrane and in the cytoplasm especially in the trans-Golgi network and endoplasmic reticulum. Differential centrifugation and receptor binding experiments suggest SUMOylation leads to inactivation of the 5-HT1AR, but further studies are needed to confirm this conclusion. Treatment with a 5-HT1AR agonist, increases the SUMOylated receptors which is further increased by treatment with estradiol, treatments that at pharmacological doses or with chronic use lead to desensitization of the 5-HT1A. Protein inhibitor of activated STAT xα (PiasXα) facilitates the SUMOylation of the 5-HT1AR, and treatment with estradiol and a 5-HT1AR agonist increases PiasXα. However, the mechanisms regulating the increase in 5-HT1AR SUMOylation with 5-HT1AR agonist treatment alone are not known. We hypothesize that sentrin proteases (SENPs) catalyze the deSUMOylation of the 5-HT1AR are reduced with agonist treatment; however, currently, there is limited knowledge regarding which of these enzymes are involved in the deSUMOylation of 5-HT1AR. Thus, the goal of this study is to determine which SENPs are involved in the deSUMOylation of 5-HT1AR. We can then determine if those enzymes are altered by treatment with 5-HT1AR agonist. In the present studies, we found that 5-HT1AR expression is maximal at 32 hours post transfection in Neuroblastoma (N2a) cells. Then, we transfected N2a cells to overexpress SENPs to determine which SENPs are involved in the deSUMOylation of the 5-HT1AR. The results suggest that SENP2 catalyzes the deSUMOylation of the 5-HT1AR when 5-HT1AR and SUMO-1 were overexpressed in N2a cells. Further, we determined that there were two isoforms of SENP2 two SENP2 isoforms at 50 kDa and 60 kDa in the rat frontal cortex and examined whether 8-OH-DPAT, a 5-HT1AR agonist, treatment decreased expression of either isoform. Our results suggest that the levels of 60 kDa SENP2 isoform were significantly decreased with 8-OH-DPAT treatment while levels of the 50 kDa did not change. These studies suggest that increase in SUMOylation of 5-HT1ARs due to 8-OH-DPAT treatment may be mediated through a decrease in 60 kDa isoform of SENP2, but further experiments are needed to confirm this conclusion. These studies to understand the mechanism involved in the regulation and specifically SUMOylation of 5-HT1AR will inform the development of new potential targets for the treatment of anxiety and depression.
    URI
    http://hdl.handle.net/1808/29849
    Collections
    • Pharmacy Dissertations and Theses [118]
    • Theses [3797]

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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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