The Interface of Nuclear and Membrane Steroid Signaling

Abstract

Steroid hormones bind receptors in the cell nucleus and in the cell membrane. The most widely studied class of steroid hormone receptors are the nuclear receptors, named for their function as ligand-dependent transcription factors in the cell nucleus. Nuclear receptors, such as estrogen receptor alpha, can also be anchored to the plasma membrane, where they respond to steroids by activating signaling pathways independent of their function as transcription factors. Steroids can also bind integral membrane proteins, such as the G protein-coupled estrogen receptor. Membrane estrogen and progestin receptors have been cloned and characterized in vitro and influence the development and function of many organ systems. Membrane androgen receptors were cloned and characterized in vitro, but their function as androgen receptors in vivo is unresolved. We review the identity and function of membrane proteins that bind estrogens, progestins and androgens. We discuss evidence that membrane glucocorticoid and mineralocorticoid receptors exist, and whether glucocorticoid and mineralocorticoid nuclear receptors act at the cell membrane. In many cases, integral membrane steroid receptors act independently of nuclear steroid receptors, even though they may share a ligand.

Beyond the X Factor: Relevance of Sex Hormones in NAFLD Pathophysiology

“…Like ERs, AR can regulate the transcriptional activation of many other genes by binding to DNA regions other than ARE, through the recruitment of other transcription factors such as AP-1, nuclear factor-κB (NF-κB), and sex-determining region Y [ 163 ] ( Figure 2 ). Androgen effects can be mediated by AR also via non-genomic signaling pathways, including the MAPK (mitogen-activated protein kinase) and the PI3K/AKT (phosphatidylinositol-3-kinase/AKT) pathways, or by the membrane-associated AR as well as by other plasma membrane associated receptors, including the epidermal growth factor receptor (EGFR) [ 164 , 165 , 166 ] ( Figure 2 ). In rodents, the hepatic expression of AR is several-fold higher in males than in females and changes with age, increasing with puberty and gradually declining with aging [ 140 ].…”

CmPn signaling networks in the tumorigenesis of breast cancer

“…It is important to mention that steroid hormones bind either nuclear receptors or membrane receptors. However, the most studied class of steroid hormone receptors are the nuclear receptors due to their early discoveries ( 20 ). Similarly, although the term “sex hormone” in hormone-dependent/-responsive/-sensitive breast cancers can be referred to either E or PRG ( 14 ), it usually refers only to E ( 21 , 22 ).…”

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

“…In addition to the nSR known as Androgen Receptor (AR), other molecular mediators of the androgenic action include different plasma membrane receptors, namely, the Zinc Transporter Member 9 (ZIP9), the Oxoeicosanoid Receptor 1 (OXER1), the G protein-coupled receptor family C group 6 member A (GPRC6A), the Ca 2+ channel Transient Receptor Potential Cation Channel Subfamily M (Melastatin) Member 8 (TRPM8) [ 9 ], and the L-type Voltage-dependent Calcium Channel (CaV1.2) [ 10 ].…”

“…However, other molecular mediators of estrogenic action are located at the cellular plasma membrane and include G-Protein Estrogen Receptor (GPER), ERx, ER-X and Gq-coupled membrane Estrogen Receptor (Gq-mER) [ 72 ]. In addition, Voltage-Gated Sodium Channel Nav1.2 is also reported to bind estrogens and to activate molecular cascades upon their binding [ 10 ].…”