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GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus
dc.contributor.author | McAllister, Carrie E. | |
dc.contributor.author | Mi, Zhen | |
dc.contributor.author | Mure, Minae | |
dc.contributor.author | Li, Qian | |
dc.contributor.author | Muma, Nancy A. | |
dc.date.accessioned | 2017-06-27T17:48:35Z | |
dc.date.available | 2017-06-27T17:48:35Z | |
dc.date.issued | 2014 | |
dc.identifier.citation | McAllister, C. E., Mi, Z., Mure, M., Li, Q., & Muma, N. A. (2014). GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus. Neuroendocrinology, 100(0), 228–239. http://doi.org/10.1159/000369467 | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/24651 | |
dc.description | The final, published version of this article is available at http://www.karger.com/?doi=10.1159/000369467. | en_US |
dc.description.abstract | Hyperactivity of the hypothalamic-pituitary-adrenal axis is a consistent biological characteristic of depression and response normalization coincides with clinical responsiveness to antidepressant medications. Desensitization of serotonin 1A receptor (5-HT1AR) signaling in the hypothalamic paraventricular nucleus (PVN) follows selective serotonin reuptake inhibitor (SSRI) antidepressant treatment and contributes to the antidepressant response. Estradiol alone produces a partial desensitization of 5-HT1AR signaling, and synergizes with SSRIs to result in a complete and more rapid desensitization than with SSRIs alone as measured by a decrease in the oxytocin and adrenocorticotrophic hormone(ACTH) responses to 5-HT1AR stimulation. G protein-coupled estrogen receptor1 (GPER1) is necessary for estradiol-induced desensitization of 5-HT1AR signaling, although the underlying mechanisms are still unclear. We now find that stimulation of GPER1 with the selective agonist G-1 and non-selective stimulation of estrogen receptors dramatically alter isoform expression of a key component of the 5-HT1AR signaling pathway, RGSz1, a GTPase activating protein selective for Gαz, the Gα subunit necessary for 5-HT1AR-mediated hormone release. RGSz1 isoforms are differentially glycosylated, SUMOylated, and phosphorylated, and differentially distributed in subcellular organelles. High molecular weight RGSz1 is SUMOylated and glycosylated, localized to the detergent-resistant microdomain (DRM) of the cell membrane, and increased by estradiol and G-1 treatment. Because activated Gαz also localizes to the DRM, increased DRM-localized RGSz1 by estradiol and G-1could reduce Gαz activity, functionally uncoupling 5-HT1AR signaling. Peripheral G-1 treatment produced partial reduction in oxytocin and ACTH responses to 5-HT1AR-stimulation similar to direct injections into the PVN. Together, these results identify GPER1 and RGSz1 as novel targets for the treatment of depression. | en_US |
dc.publisher | Karger Publishers | en_US |
dc.subject | 5-HT1A receptor | en_US |
dc.subject | GPER1 | en_US |
dc.subject | Estradiol | en_US |
dc.subject | RGSz1 | en_US |
dc.subject | G-1 | en_US |
dc.subject | SUMOylation | en_US |
dc.subject | Phosphorylation | en_US |
dc.subject | Glycosylation | en_US |
dc.subject | HPA | en_US |
dc.title | GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus | en_US |
dc.type | Article | en_US |
kusw.kuauthor | McAllister, Carrie E. | |
kusw.kuauthor | Mi, Zhen | |
kusw.kuauthor | Mure, Minae | |
kusw.kuauthor | Li, Qian | |
kusw.kuauthor | Muma, Nancy A. | |
kusw.kudepartment | Pharmacy | en_US |
dc.identifier.doi | 10.1159/000369467 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.identifier.pmid | PMC4305009 | en_US |
dc.rights.accessrights | openAccess |
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