PMID- 33339644 OWN - NLM STAT- MEDLINE DCOM- 20220104 LR - 20220104 IS - 1432-0436 (Electronic) IS - 0301-4681 (Linking) VI - 118 DP - 2021 Mar-Apr TI - Role of nuclear and membrane estrogen signaling pathways in the male and female reproductive tract. PG - 24-33 LID - S0301-4681(20)30074-8 [pii] LID - 10.1016/j.diff.2020.11.002 [doi] AB - Estrogen signaling through the main estrogen receptor, estrogen receptor 1 (ESR1; also known as ERalpha), is essential for normal female and male reproductive function. Historically, studies of estrogen action have focused on the classical genomic pathway. Although this is clearly the major pathway for steroid hormone actions, these hormones also signal through rapid non-classical effects involving cell membrane actions. Reports of rapid effects of estrogens extend for more than half a century, but recent results have expanded understanding of the identity, structure, function and overall importance of membrane receptors in estrogen responses. Key findings in this field were the immunohistochemical detection of ESR1 in cell membranes and demonstration that a portion of newly synthesized ESR1 is routed to the membrane by palmitoylation. These receptors in the membrane can then signal through protein kinases and other mechanisms following ligand binding to alter cell function. Another crucial advance in the field was development of transgenic mice expressing normal amounts of functional nuclear ESR1 (nESR1) but lacking membrane ESR1 (mESR1). Both male and female transgenic mice lacking mESR1 were infertile as adults, and both sexes had extensive reproductive abnormalities. Transgenic mice lacking mESR1 were highly protected from deleterious effects of neonatal estrogen administration, and estrogen effects on the histone methyltransferase Enhancer of Zeste homolog 2 that are mediated through mESR1 could have significant effects on epigenetic imprinting. In summary, signaling through mESR1 is essential for normal male and female reproductive function and fertility, and is a critical enabler of normal estrogen responses in vivo. Although the precise role of mESR1 in estrogen responses remains to be established, future research in this area should clarify its mechanism of action and lead to a better understanding of how mESR1 signaling works with classical genomic signaling through nESR1 to promote full estrogenic responses. CI - Copyright (c) 2020. Published by Elsevier B.V. FAU - Cooke, Paul S AU - Cooke PS AD - Department of Physiological Sciences, University of Florida, Gainesville, FL, 32610, USA. Electronic address: paulscooke@ufl.edu. FAU - Mesa, Ana M AU - Mesa AM AD - Department of Physiological Sciences, University of Florida, Gainesville, FL, 32610, USA. FAU - Sirohi, Vijay K AU - Sirohi VK AD - Department of Physiological Sciences, University of Florida, Gainesville, FL, 32610, USA. FAU - Levin, Ellis R AU - Levin ER AD - Division of Endocrinology, Department of Medicine, University of California, Irvine, Irvine, CA, 92697, USA; Department of Veterans Affairs Medical Center, Long Beach, Long Beach, CA, 90822, USA. LA - eng PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20201209 PL - England TA - Differentiation JT - Differentiation; research in biological diversity JID - 0401650 RN - 0 (Esr1 protein, mouse) RN - 0 (Estrogen Receptor alpha) RN - EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein) RN - EC 2.1.1.43 (Ezh2 protein, mouse) SB - IM MH - Animals MH - Cell Membrane/genetics MH - Cell Nucleus/*genetics MH - Enhancer of Zeste Homolog 2 Protein/*genetics MH - Epigenesis, Genetic/genetics MH - Estrogen Receptor alpha/*genetics MH - Female MH - Genitalia/*metabolism/physiology MH - Genitalia, Female/metabolism/physiology MH - Genitalia, Male/metabolism/physiology MH - Genomic Imprinting/genetics MH - Humans MH - Male MH - Mice, Transgenic/genetics MH - Signal Transduction/genetics OTO - NOTNLM OT - Efferent ducts OT - Estrogen OT - Receptor OT - Testis OT - Uterus EDAT- 2020/12/20 06:00 MHDA- 2022/01/05 06:00 CRDT- 2020/12/19 05:21 PHST- 2020/11/01 00:00 [received] PHST- 2020/11/02 00:00 [accepted] PHST- 2020/12/20 06:00 [pubmed] PHST- 2022/01/05 06:00 [medline] PHST- 2020/12/19 05:21 [entrez] AID - S0301-4681(20)30074-8 [pii] AID - 10.1016/j.diff.2020.11.002 [doi] PST - ppublish SO - Differentiation. 2021 Mar-Apr;118:24-33. doi: 10.1016/j.diff.2020.11.002. Epub 2020 Dec 9.