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dc.contributor.advisorMuma, Nancy
dc.contributor.authorMcAllister, Carrie E.
dc.date.accessioned2016-10-11T15:35:24Z
dc.date.available2016-10-11T15:35:24Z
dc.date.issued2013-12-31
dc.date.submitted2013
dc.identifier.otherhttp://dissertations.umi.com/ku:13178
dc.identifier.urihttp://hdl.handle.net/1808/21627
dc.description.abstractDepression is a common psychiatric illness, affecting over 120 million people worldwide. Women are affected disproportionately compared to men, and a large body of clinical evidence suggests a role for changes in estrogen levels in the etiology of depression. Successful selective serotonin reuptake inhibitor (SSRI) antidepressant treatment is frequently correlated with normalization of HPA axis activity. It can take several weeks to begin to see therapeutic effects of SSRIs; this therapeutic lag is thought to be due in part to the time it takes for desensitization of 5-HT1A receptor signaling in the paraventricular nucleus (PVN) of the hypothalamus to occur. It takes up to seven days of chronic SSRI treatment to desensitize 5-HT1AR signaling, but this effect is accelerated by estradiol (EB) treatment. Understanding estradiol modulation of 5-HT1AR signaling will be important for the development of improved SSRI therapy for the treatment of depression. The purpose of this dissertation therefore was to identify the mechanisms underlying EB-induced desensitization of 5-HT1AR signaling. To test the hypothesis that signaling through GPR30 is necessary for EB-induced desensitization of 5-HT1AR signaling, GPR30 protein expression in the PVN was knocked down via adenoviral vector delivery of siRNA against GPR30. Reduction of GPR30 protein expression prevented EB-induced desensitization of 5-HT1AR signaling. To test whether stimulation of GPR30 is sufficient for desensitization of 5-HT1AR signaling, rats were treated for two days with systemic injections of the selective GPR30 agonist G-1 or EB. G-1 and EB treatment both reduced the hormone responses to 5-HT1AR stimulation. To investigate the effects of GPR30 stimulation on 5-HT1AR signaling at the molecular level, changes in protein and mRNA levels of 5-HT1AR, Gαz, GPR30, and RGSz1 were examined after EB and G-1 treatment. EB treatment produced a decrease in 5-HT1AR protein, while both EB and G-1 treatment increased RGSz1 mRNA and altered expression of several RGSz1 proteins, leading to the hypothesis that alteration in RGSz1 expression and posttranslational modification underlies estradiol-induced desensitization of 5-HT1AR signaling. In particular, EB and G-1 treatment increased localization of sumoylated and glycosylated RGSz1 in the detergent resistant microdomain of the plasma membrane, where it could physically interact with and inactivate Gαz protein. The effects of GPR30 signaling, such as a decrease in 5-HT1AR protein and increase of RGSz1 isoforms, on the 5-HT1AR signaling pathway are not seen after SSRI treatment, suggesting a mechanism by which estradiol acts separately and synergistically with SSRIs to accelerate desensitization of 5-HT1AR signaling. Improving the therapeutic efficacy of SSRIs through selective targeting of GPR30 and RGSz1 could have important clinical relevance for the treatment of depression.
dc.format.extent131 pages
dc.language.isoen
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectNeurosciences
dc.subject5-HT1A receptor
dc.subjectEstradiol
dc.subjectG-1
dc.subjectGPR30
dc.subjectRGSz1
dc.subjectsumoylation
dc.titleEstradiol-induced desensitization of 5-HT1A receptor signaling
dc.typeDissertation
dc.contributor.cmtememberLi, Qian
dc.contributor.cmtememberCarrasco, Gonzalo
dc.contributor.cmtememberMcCarson, Kenneth
dc.contributor.cmtememberMure, Minae
dc.thesis.degreeDisciplineNeurosciences
dc.thesis.degreeLevelPh.D.
dc.provenance04/04/2017: The ETD release form is attached to this record as a license file.
dc.rights.accessrightsopenAccess


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