Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease

Overview

Journal Endocr Rev

Publisher Oxford University Press

Specialty Endocrinology

Date 2021 Nov 18

PMID 34791092

Citations 32

Authors

Franck Mauvais-Jarvis

Carol A Lange

Ellis R Levin

Affiliations

Soon will be listed here.

Abstract

Rapid effects of steroid hormones were discovered in the early 1950s, but the subject was dominated in the 1970s by discoveries of estradiol and progesterone stimulating protein synthesis. This led to the paradigm that steroid hormones regulate growth, differentiation, and metabolism via binding a receptor in the nucleus. It took 30 years to appreciate not only that some cellular functions arise solely from membrane-localized steroid receptor (SR) actions, but that rapid sex steroid signaling from membrane-localized SRs is a prerequisite for the phosphorylation, nuclear import, and potentiation of the transcriptional activity of nuclear SR counterparts. Here, we provide a review and update on the current state of knowledge of membrane-initiated estrogen (ER), androgen (AR) and progesterone (PR) receptor signaling, the mechanisms of membrane-associated SR potentiation of their nuclear SR homologues, and the importance of this membrane-nuclear SR collaboration in physiology and disease. We also highlight potential clinical implications of pathway-selective modulation of membrane-associated SR.

Citing Articles

Structural analysis and core promoter prediction of STAR gene and its regulatory mechanism of progesterone synthesis in bovine luteal cells.

Zhao Z, Fei G, Miao T, Liu Y, Yang J, Liang Y Sci Rep. 2025; 15(1):7746.

PMID: 40044781 PMC: 11882882. DOI: 10.1038/s41598-025-92446-2.

A Pan-Cancer Analysis of Age and Sex Differences in Cancer Incidence and Survival in the United States, 2001-2020.

Selvaraj R, Cioffi G, Waite K, Jackson S, Barnholtz-Sloan J Cancers (Basel). 2025; 17(3).

PMID: 39941747 PMC: 11815994. DOI: 10.3390/cancers17030378.

Mammary Cancer Models: An Overview from the Past to the Future.

Silva J, Oliveira P, Duarte J, Faustino-Rocha A In Vivo. 2024; 39(1):1-16.

PMID: 39740866 PMC: 11705154. DOI: 10.21873/invivo.13800.

Identification of an ionic mechanism for ERα-mediated rapid excitation in neurons.

Yu M, Yin N, Feng B, Gao P, Yu K, Liu H Sci Adv. 2024; 10(40):eadp0696.

PMID: 39356770 PMC: 11446276. DOI: 10.1126/sciadv.adp0696.

Beyond reproduction: unraveling the impact of sex hormones on cardiometabolic health.

Xega V, Liu J Med Rev (2021). 2024; 4(4):284-300.

PMID: 39135604 PMC: 11317208. DOI: 10.1515/mr-2024-0012.

References

Peluso J, Pru C, Liu X, Kelp N, Pru J . Progesterone receptor membrane component 1 and 2 regulate granulosa cell mitosis and survival through a NFΚB-dependent mechanism†. Biol Reprod. 2019; 100(6):1571-1580. PMC: 6561858. DOI: 10.1093/biolre/ioz043. View

Condon J, Hardy D, Kovaric K, Mendelson C . Up-regulation of the progesterone receptor (PR)-C isoform in laboring myometrium by activation of nuclear factor-kappaB may contribute to the onset of labor through inhibition of PR function. Mol Endocrinol. 2005; 20(4):764-75. DOI: 10.1210/me.2005-0242. View

Menazza S, Sun J, Appachi S, Chambliss K, Kim S, Aponte A . Non-nuclear estrogen receptor alpha activation in endothelium reduces cardiac ischemia-reperfusion injury in mice. J Mol Cell Cardiol. 2017; 107:41-51. PMC: 5514412. DOI: 10.1016/j.yjmcc.2017.04.004. View

Leung J, Sadar M . Non-Genomic Actions of the Androgen Receptor in Prostate Cancer. Front Endocrinol (Lausanne). 2017; 8:2. PMC: 5239799. DOI: 10.3389/fendo.2017.00002. View

Lee H, Yea K, Kim J, Lee B, Chae Y, Kim H . Epidermal growth factor increases insulin secretion and lowers blood glucose in diabetic mice. J Cell Mol Med. 2007; 12(5A):1593-604. PMC: 3918075. DOI: 10.1111/j.1582-4934.2007.00169.x. View

Notas G, Kampa M, Castanas E . G Protein-Coupled Estrogen Receptor in Immune Cells and Its Role in Immune-Related Diseases. Front Endocrinol (Lausanne). 2020; 11:579420. PMC: 7564022. DOI: 10.3389/fendo.2020.579420. View

Pedram A, Razandi M, Deschenes R, Levin E . DHHC-7 and -21 are palmitoylacyltransferases for sex steroid receptors. Mol Biol Cell. 2011; 23(1):188-99. PMC: 3248897. DOI: 10.1091/mbc.E11-07-0638. View

Jacovetti C, Abderrahmani A, Parnaud G, Jonas J, Peyot M, Cornu M . MicroRNAs contribute to compensatory β cell expansion during pregnancy and obesity. J Clin Invest. 2012; 122(10):3541-51. PMC: 3461923. DOI: 10.1172/JCI64151. View

Lee S, Heo J, Jo S, Kim G, Kim S, Yoo H . Progesterone receptor membrane component 1 reduces cardiac steatosis and lipotoxicity via activation of fatty acid oxidation and mitochondrial respiration. Sci Rep. 2021; 11(1):8781. PMC: 8062525. DOI: 10.1038/s41598-021-88251-2. View

10.

Patino R, Thomas P . Gonadotropin stimulates 17 alpha,20 beta,21-trihydroxy-4-pregnen-3-one production from endogenous substrates in Atlantic croaker ovarian follicles undergoing final maturation in vitro. Gen Comp Endocrinol. 1990; 78(3):474-8. DOI: 10.1016/0016-6480(90)90036-l. View

11.

Du G, Zhou L, Chen X, Wan X, He Y . The G protein-coupled receptor GPR30 mediates the proliferative and invasive effects induced by hydroxytamoxifen in endometrial cancer cells. Biochem Biophys Res Commun. 2012; 420(2):343-9. DOI: 10.1016/j.bbrc.2012.02.161. View

12.

Roque C, Mendes-Oliveira J, Duarte-Chendo C, Baltazar G . The role of G protein-coupled estrogen receptor 1 on neurological disorders. Front Neuroendocrinol. 2019; 55:100786. DOI: 10.1016/j.yfrne.2019.100786. View

13.

Chang C, Kokontis J, Liao S . Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science. 1988; 240(4850):324-6. DOI: 10.1126/science.3353726. View

14.

Perez Kerkvliet C, Dwyer A, Diep C, Oakley R, Liddle C, Cidlowski J . Glucocorticoid receptors are required effectors of TGFβ1-induced p38 MAPK signaling to advanced cancer phenotypes in triple-negative breast cancer. Breast Cancer Res. 2020; 22(1):39. PMC: 7193415. DOI: 10.1186/s13058-020-01277-8. View

15.

Cinar B, Mukhopadhyay N, Meng G, Freeman M . Phosphoinositide 3-kinase-independent non-genomic signals transit from the androgen receptor to Akt1 in membrane raft microdomains. J Biol Chem. 2007; 282(40):29584-93. DOI: 10.1074/jbc.M703310200. View

16.

Thomas P, Pang Y, Dong J . Membrane androgen receptor characteristics of human ZIP9 (SLC39A) zinc transporter in prostate cancer cells: Androgen-specific activation and involvement of an inhibitory G protein in zinc and MAP kinase signaling. Mol Cell Endocrinol. 2017; 447:23-34. DOI: 10.1016/j.mce.2017.02.025. View

17.

Pepermans R, Sharma G, Prossnitz E . G Protein-Coupled Estrogen Receptor in Cancer and Stromal Cells: Functions and Novel Therapeutic Perspectives. Cells. 2021; 10(3). PMC: 8002620. DOI: 10.3390/cells10030672. View

18.

Meyer M, Rosemann T, Barton M, Prossnitz E . GPER Mediates Functional Endothelial Aging in Renal Arteries. Pharmacology. 2017; 100(3-4):188-193. PMC: 5558788. DOI: 10.1159/000478732. View

19.

Pi M, Kapoor K, Wu Y, Ye R, Senogles S, Nishimoto S . Structural and Functional Evidence for Testosterone Activation of GPRC6A in Peripheral Tissues. Mol Endocrinol. 2015; 29(12):1759-73. PMC: 4664231. DOI: 10.1210/me.2015-1161. View

20.

Wang H, de Bari O, Arnatt C, Liu M, Portincasa P, Wang D . Activation of Estrogen Receptor G Protein-Coupled Receptor 30 Enhances Cholesterol Cholelithogenesis in Female Mice. Hepatology. 2020; 72(6):2077-2089. PMC: 8157628. DOI: 10.1002/hep.31212. View