GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus.
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 of the hypothalamus (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 receptor 1 (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 nonselective 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-1 could reduce Gαz activity, functionally uncoupling 5-HT1AR signaling. Peripheral G-1 treatment produced a 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.
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kans., USA.
Carrie E
CE
McAllister
Zhen
Z
Mi
Minae
M
Mure
Qian
Q
Li
Nancy A
NA
Muma
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D002491:Central Nervous System Agents / Q000494:pharmacology; D003517:Cyclopentanes / Q000494:pharmacology; D004958:Estradiol / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D006031:Glycosylation; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D015388:Organelles / Q000378:metabolism; D010766:Phosphorylation; D020033:Protein Isoforms; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology; D020710:RGS Proteins / Q000378:metabolism*; D011897:Random Allocation; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction; D058207:Sumoylation
C517943:1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone; D002491:Central Nervous System Agents; D003517:Cyclopentanes; D004967:Estrogens; C520305:Gper1 protein, rat; D020033:Protein Isoforms; D011804:Quinolines; D020710:RGS Proteins; D043562:Receptors, G-Protein-Coupled; C492955:Rgs20 protein, rat; D044282:Receptor, Serotonin, 5-HT1A; D004958:Estradiol