Progesterone and estrogen regulate NALCN expression in human myometrial smooth muscle cells

Amazu, Chinwendu; Ma, Xiaofeng; Henkes, Clara; Ferreira, Juan J.; Santi, Celia M.; England, Sarah K.

doi:10.1152/ajpendo.00320.2019

Cited by 14 publications

(20 citation statements)

References 80 publications

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“…suggesting that oxytocin has a sustained effect on the VDCC-dependent intracellular Ca 2+ concentration in MSMCs from pregnant rats (Arnaudeau, Lepretre, & Mironneau, 1994). We also recently demonstrated that NALCN expression and activity are regulated by the hormones progesterone and estrogen (Amazu et al, 2020).…”

Section: Discussionmentioning

confidence: 69%

“…*P<0.05, ** P<0.01, and *** P<0.001 by (D, E) unpaired t-test or (G,H) paired t-test. During the quiescent state, progesterone binding to the progesterone receptor (PR A/B ) increases NALCN expression and activity (Amazu et al, 2020). Sodium current through NALCN activates SLO2.1 channels, increasing K + efflux to maintain the cell in a hyperpolarized state.…”

Section: Statistical Analysesmentioning

confidence: 99%

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A novel sodium signaling complex regulates uterine activity

Ferreira

Amazu

Molina

et al. 2020

Preprint

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At the end of pregnancy, the uterus transitions from a quiescent state to an excitable, contractile state. These changes are linked to depolarization of the myometrial smooth muscle cell (MSMC) resting membrane potential. The membrane potential is primarily determined by the balance between an outward potassium (K+) leak current and an inward sodium (Na+) leak current. We recently described a Na+-activated K+ channel (SLO2.1) and a non-selective Na+ leak channel (NALCN) in human MSMCs. Here, we asked whether these channels function together. We show that SLO2.1 currents are activated by an inward NALCN-dependent Na+ leak current, leading to MSMC hyperpolarization. The regulation of the membrane potential by NALCN/SLO2.1 activity modulates both Ca2+ entry through VDCCs, and myometrial contractility. Finally, NALCN and SLO2.1 are in proximity to one another in human MSMCs. We conclude that SLO2.1 and NALCN function together to regulate human MSMC membrane potential and excitability.

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Section: Discussionmentioning

confidence: 69%

Section: Statistical Analysesmentioning

confidence: 99%

A novel sodium signaling complex regulates uterine activity

Ferreira

Amazu

Molina

et al. 2020

Preprint

Self Cite

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show abstract

“…These results were in line with data published by Arnaudeau et al., suggesting that oxytocin has a sustained effect on the VDCC-dependent intracellular Ca 2+ concentration in MSMCs from pregnant rats ( Arnaudeau et al., 1994 ). We also recently demonstrated that NALCN expression and activity are regulated by the hormones progesterone and estrogen ( Amazu et al., 2020 ).…”

Section: Discussionmentioning

confidence: 99%

SLO2.1/NALCN a sodium signaling complex that regulates uterine activity

et al. 2021

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Summary Depolarization of the myometrial smooth muscle cell (MSMC) resting membrane potential is necessary for the uterus to transition from a quiescent state to a contractile state. The molecular mechanisms involved in this transition are not completely understood. Here, we report that a coupled system between the Na + -activated K + channel (SLO2.1) and the non-selective Na + leak channel (NALCN) determines the MSMC membrane potential. Our data indicate that Na + entering through NALCN acts as an intracellular signaling molecule that activates SLO2.1. Potassium efflux through SLO2.1 hyperpolarizes the membrane. A decrease in SLO2.1/NALCN activity induces membrane depolarization, triggering Ca 2+ entry through voltage-dependent Ca 2+ channels and promoting contraction. Consistent with functional coupling, our data show that NALCN and SLO2.1 are in close proximity in human MSMCs. We propose that these arrangements of SLO2.1 and NALCN permit these channels to functionally regulate MSMC membrane potential and cell excitability and modulate uterine contractility.

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“…Indeed, differential enrichment of transcription factor motifs suggests the involvement of cofactors that regulate transcriptional activation or repression depending on the cell type or environmental context. These cofactors may determine E2 regulation in the cortex and muscle, respectively, of Bcas1 , required for myelination, and the sodium leak channel, Nalcn ( Humphreys et al, 2014 ; Amazu et al, 2020 ). Interestingly, treatment induced CpG hypomethylation of hormone response genes, limited to young and middle-age animals, mainly occurred at intergenic regions or within introns ( Table 1 ).…”

Section: Discussionmentioning

confidence: 99%

Examination of CA1 Hippocampal DNA Methylation as a Mechanism for Closing of Estrogen’s Critical Window

Sinha

Rani

Kumar

et al. 2021

Front. Aging Neurosci.

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There is a critical window for estrogen replacement therapy, beyond which estradiol (E2) fails to enhance cognition and N-methyl-D-aspartate (NMDA) receptor function, and E2-responsive transcription decreases. Much less attention has been given to the mechanism for closing of the critical window, which is thought to involve the decline in estrogen signaling cascades, possibly involving epigenetic mechanisms, including DNA methylation. This study investigated changes in DNA methylation in region CA1 of the hippocampus of ovariectomized female rats over the course of brain aging and in response to E2-treatment, using whole genome bisulfite sequencing. Differential methylation of CpG and non-CpG (CHG and CHH) sites and associated genes were characterized in aged controls (AC), middle-age controls (MC), and young controls (YC) and differential methylation in response to E2-treatment (T) was examined in each age group (AT-AC, MT-MC, and YT-YC). Possible candidate genes for the closing of the critical window were defined as those that were hypomethylated by E2-treatment in younger animals, but were unresponsive in aged animals. Gene ontology categories for possible critical window genes were linked to response to hormones (Adcyap1, Agtr2, Apob, Ahr, Andpro, Calm2, Cyp4a2, Htr1b, Nr3c2, Pitx2, Pth, Pdk4, Slc2a2, Tnc, and Wnt5a), including G-protein receptor signaling (Gpr22 and Rgs4). Other possible critical window genes were linked to glutamate synapses (Nedd4, Grm1, Grm7, and Grin3a). These results suggest that decreased E2 signaling with advanced age, and/or prolonged E2 deprivation, results in methylation of E2-responsive genes, including those involved in rapid E2 signaling, which may limit subsequent transcription.

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Progesterone and estrogen regulate NALCN expression in human myometrial smooth muscle cells

Cited by 14 publications

References 80 publications

A novel sodium signaling complex regulates uterine activity

A novel sodium signaling complex regulates uterine activity

SLO2.1/NALCN a sodium signaling complex that regulates uterine activity

Examination of CA1 Hippocampal DNA Methylation as a Mechanism for Closing of Estrogen’s Critical Window

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