Rapid estrogen actions on ion channels: A survey in search for mechanisms

Kow, Lee‐Ming; Pfaff, Donald W.

doi:10.1016/j.steroids.2016.02.018

Cited by 48 publications

(38 citation statements)

References 183 publications

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“…The same laboratory later demonstrated that oestrogen directly interacts with the LTCC protein and inhibits LTCC current even at resting state on cultured HEK293 cells . Indeed, similar observations have been reported for a broad range of ion channels (see review). Research on the rapid non‐genomic roles of oestrogen has been primarily focused on the membranous receptors.…”

Section: Er Activation Signalling Pathways and Cell Functionssupporting

confidence: 62%

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

et al. 2017

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Oestrogen receptors (ERs) and β‐adrenergic receptors (βARs) play important roles in the cardiovascular system. Moreover, these receptors are expressed in cardiac myocytes and vascular tissues. Numerous experimental observations support the hypothesis that similarities and interactions exist between the signalling pathways of ERs (ERα, ERβ and GPR30) and βARs (β1AR, β2AR and β3AR). The recently discovered oestrogen receptor GPR30 shares structural features with the βARs, and this forms the basis for the interactions and functional overlap. GPR30 possesses protein kinase A (PKA) phosphorylation sites and PDZ binding motifs and interacts with A‐kinase anchoring protein 5 (AKAP5), all of which enable its interaction with the βAR pathways. The interactions between ERs and βARs occur downstream of the G‐protein‐coupled receptor, through the Gαs and Gαi proteins. This review presents an up‐to‐date description of ERs and βARs and demonstrates functional synergism and interactions among these receptors in cardiac cells. We explore their signalling cascades and the mechanisms that orchestrate their interactions and propose new perspectives on the signalling patterns for the GPR30 based on its structural resemblance to the βARs. In addition, we explore the relevance of these interactions to cell physiology, drugs (especially β‐blockers and calcium channel blockers) and cardioprotection. Furthermore, a receptor‐independent mechanism for oestrogen and its influence on the expression of βARs and calcium‐handling proteins are discussed. Finally, we highlight promising therapeutic avenues that can be derived from the shared pathways, especially the phosphatidylinositol‐3‐OH kinase (PI3K/Akt) pathway.

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Section: Er Activation Signalling Pathways and Cell Functionssupporting

confidence: 62%

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

et al. 2017

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“…These drugs act as estrogen receptor agonists or antagonists, depending on the tissue, and are used for treating breast cancer and osteoporosis [66]. Off-target effects of these drugs are more than likely related to well-known rapid non-genomic actions of estrogen [67]. Indeed, inhibition of both viral entry and TPC activity by submicromolar concentrations of raloxifene is striking.…”

Section: Discussionmentioning

confidence: 99%

Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers

Penny

Vassileva

Jha

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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A B S T R A C TTwo-pore channels (TPCs) are Ca 2+ -permeable ion channels localised to the endo-lysosomal system where they regulate trafficking of various cargoes including viruses. As a result, TPCs are emerging as important drug targets. However, their pharmacology is ill-defined. There are no approved drugs to target them. And their mechanism of ligand activation is largely unknown. Here, we identify a number of FDA-approved drugs as TPC pore blockers. Using a model of the pore of human TPC2 based on recent structures of mammalian TPCs, we virtually screened a database of~1500 approved drugs. Because TPCs have recently emerged as novel host factors for Ebola virus entry, we reasoned that Ebola virus entry inhibitors may exert their effects through inhibition of TPCs. Cross-referencing hits from the TPC virtual screen with two recent high throughput anti-Ebola screens yielded approved drugs targeting dopamine and estrogen receptors as common hits. These compounds inhibited endogenous NAADP-evoked Ca 2+ release from sea urchin egg homogenates, NAADP-mediated channel activity of TPC2 re-routed to the plasma membrane, and PI(3,5)P 2 -mediated channel activity of TPC2 expressed in enlarged lysosomes. Mechanistically, single channel analyses showed that the drugs reduced mean open time consistent with a direct action on the pore. Functionally, drug potency in blocking TPC2 activity correlated with inhibition of Ebola virus-like particle entry. Our results expand TPC pharmacology through the identification of approved drugs as novel blockers, support a role for TPCs in Ebola virus entry, and provide insight into the mechanisms underlying channel regulation.

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“…As we known, the action of 17β‐E2 on different tissues and channel types showed different signaling pathways with dependent or independent of ERα expression (Alvarez‐Baron et al, ; Kow & Pfaff, ; Sarkar et al, ). In this study, the involvement of ERα in 17β‐E2‐activated Cl − currents was supported by several observations.…”

Section: Discussionmentioning

confidence: 99%

Activation of ClC‐3 chloride channel by 17β‐estradiol relies on the estrogen receptor α expression in breast cancer

Yang

Wang

et al. 2017

Journal Cellular Physiology

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Although extensively studied, the mechanisms by which estrogen promotes breast cancer growth remain to be fully elucidated. Tamoxifen, an antiestrogen agent to treat ERα+ breast cancer, is also a high-affinity blocker of the chloride channels. In this study, we explored the involvement of the chloride channels in the action of estrogen in breast cancer. We found that 17β-estradiol (17β-E2) concentration-dependently activated the chloride currents in ERα+ breast cancer MCF-7 cells. Extracellular hypertonic challenge and chloride channel blockers, NPPB and DIDS inhibited the 17β-E2-activated chloride currents. Decreased the ClC-3 protein expression caused the depletion of the 17β-E2-activated chloride currents. 17β-E2-activated chloride currents which relied on the ERα expression were demonstrated by the following evidences. Firstly, 17β-E2-activated chloride currents could not be observed in ERα- breast cancer MDA-MB-231 cells. Secondly, ER antagonists, tamoxifen and ICI 182,780, and downregulation of ERα expression inhibited or abolished the 17β-E2-activated chloride currents. Thirdly, ERα expression was induced in MDA-MB-231 cells by ESR1 gene transfection, and then 17β-E2-activated chloride currents could be observed. In MCF-7 cells, ERα and ClC-3 mainly located in nucleus and translocated to cell plasma and membrane with respect to co-localization following treatment of 17β-E2. Downregulation of ERα expression could decrease the expression of ClC-3 protein. Conversely, downregulation of ClC-3 expression did not influence the ERα expression. Taken together, our findings demonstrated that ClC-3 is a potential target of 17β-E2 and is modulated by the ERα in breast cancer cell. Pharmacological modulation of ClC-3 may provide a deep understanding in antiestrogen treatment of breast cancer patients.

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Rapid estrogen actions on ion channels: A survey in search for mechanisms

Cited by 48 publications

References 183 publications

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

Molecular pathways of oestrogen receptors and β‐adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers

Activation of ClC‐3 chloride channel by 17β‐estradiol relies on the estrogen receptor α expression in breast cancer

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