GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus

Carrie E. McAllister, Zhen Mi, Minae Mure, Qian Li, Nancy A. Muma

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 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 Gz, the G 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 Gz also localizes to the DRM, increased DRM-localized RGSz1 by estradiol and G-1 could reduce Gz 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.

Original languageEnglish (US)
Pages (from-to)228-239
Number of pages12
JournalNeuroendocrinology
Volume100
DOIs
StatePublished - Feb 6 2014
Externally publishedYes

Fingerprint

Receptor, Serotonin, 5-HT1A
Estrogen Receptor alpha
Post Translational Protein Processing
G-Protein-Coupled Receptors
Hypothalamus
Estradiol
Detergents
Antidepressive Agents
Paraventricular Hypothalamic Nucleus
Oxytocin
Adrenocorticotropic Hormone
Protein Isoforms
GTPase-Activating Proteins
Serotonin Uptake Inhibitors
Therapeutics
Estrogen Receptors
Organelles
Molecular Weight
Cell Membrane
Hormones

Keywords

  • 5-HT receptor
  • Estradiol
  • G-1
  • Glycosylation
  • GPER1
  • Hypothalamic-pituitary-adrenal axis
  • Phosphorylation
  • RGSz1
  • SUMOylation

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Endocrine and Autonomic Systems
  • Cellular and Molecular Neuroscience

Cite this

GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus. / McAllister, Carrie E.; Mi, Zhen; Mure, Minae; Li, Qian; Muma, Nancy A.

In: Neuroendocrinology, Vol. 100, 06.02.2014, p. 228-239.

Research output: Contribution to journalArticle

McAllister, Carrie E. ; Mi, Zhen ; Mure, Minae ; Li, Qian ; Muma, Nancy A. / GPER1 stimulation alters posttranslational modification of RGSz1 and induces desensitization of 5-HT1A receptor signaling in the rat hypothalamus. In: Neuroendocrinology. 2014 ; Vol. 100. pp. 228-239.
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