GPR30 is necessary for estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the rat hypothalamus

Abstract

Estrogen therapy used in combination with selective serotonin reuptake inhibitor (SSRI) treatment improves SSRI efficacy for the treatment of mood disorders. Desensitization of serotonin 1A (5-HT1A) receptors, which takes one to two weeks to develop in animals, is necessary for SSRI therapeutic efficacy. Estradiol modifies 5-HT1A receptor signaling and induces a partial desensitization in the paraventricular nucleus (PVN) of the rat within two days, but the mechanisms underlying this effect are currently unknown. The purpose of this study was to identify the estrogen receptor necessary for estradiol-induced 5-HT1A receptor desensitization. We previously showed that estrogen receptor β is not necessary for 5-HT1A receptor desensitization and that selective activation of estrogen receptor GPR30 mimics the effects of estradiol in rat PVN. Here, we used a recombinant adenovirus containing GPR30 siRNAs to decrease GPR30 expression in the PVN. Reduction of GPR30 prevented estradiol-induced desensitization of 5-HT1A receptor as measured by hormonal responses to the selective 5-HT1A receptor agonist, (+)8-OH-DPAT. To determine the possible mechanisms underlying these effects, we investigated protein and mRNA levels of 5-HT1A receptor signaling components including 5-HT1A receptor, Gαz, and RGSz1. We found that two days of estradiol increased protein and mRNA expression of RGSz1, and decreased 5-HT1A receptor protein but increased 5-HT1A mRNA; GPR30 knockdown prevented the estradiol-induced changes in 5-HT1A receptor protein in the PVN. Taken together, these data demonstrate that GPR30 is necessary for estradiol-induced changes in the 5-HT1A receptor signaling pathway and desensitization of 5-HT1A receptor signaling.

International Union of Basic and Clinical Pharmacology. XCVII. G Protein–Coupled Estrogen Receptor and Its Pharmacologic Modulators

“…GPER exhibits distinct expression patterns compared with classic ERs (Hazell et al, 2009), exemplified by expression in magnocellular oxytocin but not vasopressin neurons (Sakamoto et al, 2007). Selective GPER activation with G-1 attenuates oxytocin and ACTH responses (Xu et al, 2009) and GPER is required for E2-mediated desensitization of serotonin signaling in the paraventricular nucleus (McAllister et al, 2012). GPER is also implicated in the rapid E2-mediated release of luteinizing hormonereleasing hormone via enhanced Ca 2+ oscillations in primate luteinizing hormone-releasing hormone neurons ) as well as negative feedback by E2 of gonadotropin-releasing hormone-induced luteinizing hormone secretion (Rudolf and Kadokawa, 2013).…”

Regulators of G-Protein-Signaling Proteins: Negative Modulators of G-Protein-Coupled Receptor Signaling

“…RGSZ1 mRNA transcripts were found in multiple areas of human brain, showing higher abundance in the caudate nucleus and the temporal lobe McAllister et al, 2012;Rodriguez-Munoz et al, 2008;Sanchez-Blazquez et al, 2010;Wang et al, 1998). Despite the correlation between Ga z and RGSZ1 expression found in human brain, several regions showed significant amounts of Ga z mRNA transcripts but almost absent RGSZ1 transcripts, indicating additional Ga z GAP molecules expressed in regions where RGSZ1 is not abundant (Wang et al, 1998).…”

GPR30 mediates anorectic estrogen-induced STAT3 signaling in the hypothalamus

“…GPR30 activation has been linked to protein kinase A, protein kinase C, and the pertussis-sensitive transactivation of epidermal growth factor receptor (EGFR) [11,12]. GPR30 plays an important role in the regulation of calcium oscillations in luteinizing hormone-releasing neurons in the hypothalamus and in the control of serotonin receptor signaling in the paraventricular nucleus [13,14].…”