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G-protein Coupled Receptors

G-protein Coupled Receptors

G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.

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Estrogen Replacement Therapy in Ovariectomized Rats: Complementary Roles of ER and GPR30 in Alleviating

Siyi He¹, Zhongyu Ren¹, Lan Wu¹

¹Department of Psychiatry, Renmin Hospital of Wuhan University, Wuhan 430060, China.

Current Issues in Molecular Biology

|May 27, 2026

Summary

Estrogen deficiency exacerbates depression in menopausal models. Estrogen replacement therapy (ERT) alleviates depressive behaviors by reducing brain inflammation and supporting neural adaptation via estrogen receptors (ER).

Keywords:

GPR30 estrogen major depressive disorder neuroinflammation short-term stress

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Area of Science:

Neuroscience
Endocrinology
Psychiatry

Background:

Women exhibit a higher prevalence of major depressive disorder (MDD), with the estrogen-depression link under investigation.
Estrogen deficiency, particularly during menopause, is implicated in the onset and progression of depression.

Purpose of the Study:

To investigate the therapeutic effects of estrogen replacement therapy (ERT) on depression in a rat model simulating menopausal estrogen deficiency.
To elucidate the underlying mechanisms involving estrogen receptors (ER) and G protein-coupled estrogen receptor 30 (GPR30) in menopausal depression.

Main Methods:

Ovariectomized (OVX) rats were used to model estrogen deficiency and subjected to chronic and acute stress paradigms.
Behavioral testing, Western blotting, ELISA, LC-MS, and cell experiments were employed to assess depressive-like behaviors and molecular changes.
Key markers analyzed included ER, BDNF, inflammatory cytokines (IL-1β/IL-18), P2X7, GPR30, spine density, and microglia.

Main Results:

In chronic stress, OVX rats displayed depressive behaviors and altered hippocampal molecules; ERT significantly reduced these behaviors and reversed molecular changes, excluding GPR30.
In acute stress, ERT reduced depressive behaviors and reversed OVX-induced decreases in ER, BDNF, spine density, and microglia, while normalizing elevated P2X7, IL-1β/IL-18, and GPR30.
ERT normalized metabolic abnormalities associated with chronic unpredictable mild stress (CUMS) and demonstrated efficacy in both acute and chronic stress models.

Conclusions:

Estrogen deficiency contributes to depression in a menopause-like rat model.
ERT alleviates depressive-like behaviors by reducing neuroinflammation and enhancing neural plasticity through ER.
GPR30 plays a dual role, potentially serving as a therapeutic target for menopausal depression by modulating neuroinflammation and neuroplasticity via the NLRP3/P2X7/IL-1β pathway.