1. Academic Validation
  2. Rapid membrane effect of estrogens on stimulation of corticotropin-releasing hormone

Rapid membrane effect of estrogens on stimulation of corticotropin-releasing hormone

  • Psychoneuroendocrinology. 2020 Jul;117:104680. doi: 10.1016/j.psyneuen.2020.104680.
Yang-Jian Qi 1 Zheng Fang 1 Zhong Ren 1 Juan-Li Wu 1 Lei Guo 1 Hong Tan 1 Man-Li Huang 2 Yi Shen 3 Ai-Min Bao 4
Affiliations

Affiliations

  • 1 NHC and CAMS key laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
  • 2 Department of Mental Health, Zhejiang Province Key Laboratory of Mental Disorder's Management, National Clinical Research Center for Mental Health Disorders, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
  • 3 NHC and CAMS key laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China. Electronic address: yshen2@zju.edu.cn.
  • 4 NHC and CAMS key laboratory of Medical Neurobiology, School of Brain Science and Brain Medicine, Department of Neurology of the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China. Electronic address: baoaimin@zju.edu.cn.
Abstract

Background: Classic nuclear-initiated estrogen signaling stimulates corticotropin-releasing hormone (CRH) gene expression as a transcription factor. However, the possible mechanism by which membrane-initiated estrogen signaling (MIES) influences CRH expression remains unclear. There are indications that MIES may upregulate nitric oxide (NO) production through the phosphatidylinositol 3-hydroxy kinase (PI3K) and potentially through the mitogen-activated protein kinase (MAPK) pathway.

Objectives: We investigated the effect of MIES-mediated kinase pathways on CRH expression with or without NO synthesis.

Method: In SK-N-SH Cell Culture, estradiol-bovine serum albumin (E2-BSA) was used as the specific membrane Estrogen receptor Activator, with a specific NO donor, and/or inhibitors for NO Synthase (NOS), PI3K, MAPK, protein kinase A (PKA), and protein kinase C (PKC).

Results: E2-BSA significantly increased NO and CRH levels in the medium and NOS1-mRNA levels in the cells. In addition, NO donor up-regulated CRH expression, while NOS-inhibitor down-regulated it. When the inhibitor of MAPK and/or the inhibitor of PI3K was added to the medium, only the latter appeared to significantly block the stimulating effect of E2-BSA on NO synthesis, and this was accompanied by an increased CRH expression in the medium. We further studied the effect of the MIES-PKC-mediated pathway on CRH expression, with or without NOS-inhibitor, while the MIES-PKA(-PI3K) pathway served as a control. We found that MIES-PKC upregulated CRH expression independent of NO synthesis.

Conclusion: MIES can efficiently upregulate CRH expression via various intracellular kinase pathways and may thus be a crucial component in the stress response.

Keywords

Corticotropin-releasing hormone; Membrane estrogen receptor; Nitric oxide; Phosphatidylinositol 3-hydroxy kinase; Protein kinase C pathway.

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