A tamoxifen receptor within a voltage-gated sodium channel

Sula, Altin; Hollingworth, David; Ng, Leo C.T.; Larmore, Megan; DeCaen, Paul G.; Wallace, B.A.

doi:10.1016/j.molcel.2020.12.048

Cited by 20 publications

(22 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…NaV1.2 channel increased expression has been observed in different cancer types, including prostate [ 127 ] and ovarian cancer, where it is involved in regulating migration and invasion of highly metastatic cancer cells [ 128 ]. Interestingly, rapid estrogen actions on different ion channels’ functionality have been reported, and both endogenous and exogenous estrogens can bind NaV1.2, other VGSCs and other ion channels, to regulate their activity [ 129 , 130 ] ( Figure 2 ).…”

Section: Membrane Steroid Receptors and Their Role In Hormone-sensitive Cancersmentioning

confidence: 99%

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Masi

Racchi

Travelli

et al. 2021

Cells

View full text Add to dashboard Cite

Cancer is one of the most common causes of death worldwide, and its development is a result of the complex interaction of genetic factors, environmental cues, and aging. Hormone-sensitive cancers depend on the action of one or more hormones for their development and progression. Sex steroids and corticosteroids can regulate different physiological functions, including metabolism, growth, and proliferation, through their interaction with specific nuclear receptors, that can transcriptionally regulate target genes via their genomic actions. Therefore, interference with hormones’ activities, e.g., deregulation of their production and downstream pathways or the exposition to exogenous hormone-active substances such as endocrine-disrupting chemicals (EDCs), can affect the regulation of their correlated pathways and trigger the neoplastic transformation. Although nuclear receptors account for most hormone-related biologic effects and their slow genomic responses are well-studied, less-known membrane receptors are emerging for their ability to mediate steroid hormones effects through the activation of rapid non-genomic responses also involved in the development of hormone-sensitive cancers. This review aims to collect pre-clinical and clinical data on these extranuclear receptors not only to draw attention to their emerging role in cancer development and progression but also to highlight their dual role as tumor microenvironment players and potential candidate drug targets.

show abstract

Section: Membrane Steroid Receptors and Their Role In Hormone-sensitive Cancersmentioning

confidence: 99%

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Masi

Racchi

Travelli

et al. 2021

Cells

View full text Add to dashboard Cite

show abstract

“…Tamoxifen, a selective estrogen receptor modulator, can bind a sodium channel from Magnetococcus marinus (NavMs) and inhibit NavMs and the human homolog Nav1.2 in vitro ( 34 ). Scientists often ignore the unintended targets of estrogens.…”

Section: Membrane Estrogen Receptorsmentioning

confidence: 99%

The Interface of Nuclear and Membrane Steroid Signaling

Treviño

Gorelick

2021

Endocrinology

View full text Add to dashboard Cite

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.

show abstract

“…An eukaryotic Nav channel comprises a single 2000-residue polypeptide chain, with four homologous domains arranged in a pseudotetrameric architecture, as verified by a handful of recent cryoEM structures reported in recent years (3)(4)(5)(6)(7)(8). In contrast, bacterial Nav channels are homotetramers with ~270 residues per subunit and have a simpler architecture with smaller intracellular and extracellular domains (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Despite their limited (~25%) sequence identity, bacterial Nav channels have been shown to share drug sensitivity and other functional properties with their eukaryotic counterparts, making them compelling model systems for structure/function studies (27).…”

Section: Introductionmentioning

confidence: 96%

“…Many efforts have been made to determine the structure of Nav channels in different functional states. Bacterial Nav channels have provided some insights, including structures of at least six subtypes (NavAb, NavMs, NavRh, NavCt, NaChBac and NavAe) in apparently distinct states (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26). Still, these structures were solved in a non-native environment (at cryogenic temperatures, solubilized by detergents) and often in the presence of mutations, so their functional assignments can be ambiguous.…”

Section: Introductionmentioning

confidence: 99%

An open state of a voltage-gated sodium channel involving a π-helix and conserved pore-facing Asparagine

Choudhury

Kasimova

McComas

et al. 2021

Preprint

View full text Add to dashboard Cite

Voltage-gated sodium (Nav) channels play critical roles in propagating action potentials and otherwise manipulating ionic gradients in excitable cells. These channels open in response to membrane depolarization, selectively permeating sodium ions until rapidly inactivating. Structural characterization of the gating cycle in this channel family has proved challenging, particularly due to the transient nature of the open state. A structure from the bacterium Magnetococcus marinus Nav (NavMs) was initially proposed to be open, based on its pore diameter and voltage-sensor conformation. However, the functional annotation of this model, and the structural details of the open state, remain disputed. In this work, we used molecular modeling and simulations to test possible open-state models of NavMs. The full-length experimental structure, termed here the α-model, was consistently dehy-drated at the activation gate, indicating an inability to conduct ions. Based on a spontaneous transition observed in extended simulations, and sequence/structure comparison to other Nav channels, we built an alternative π-model featuring a helix transition and the rotation of a conserved asparagine residue into the activation gate. Pore hydration, ion permeation and state-dependent drug binding in this model were consistent with an open functional state. This work thus offers both a functional annotation of the full-length NavMS structure, and a detailed model for a stable Nav open state, with potential conservation in diverse ion-channel families.

show abstract

A tamoxifen receptor within a voltage-gated sodium channel

Cited by 20 publications

References 38 publications

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

Molecular Characterization of Membrane Steroid Receptors in Hormone-Sensitive Cancers

The Interface of Nuclear and Membrane Steroid Signaling

An open state of a voltage-gated sodium channel involving a π-helix and conserved pore-facing Asparagine

Contact Info

Product

Resources

About