Orai1 protein expression and the role of calcium release‐activated calcium channels in the contraction of human term‐pregnant and non‐pregnant myometrium

Šutovská, Martina; Kočmálová, Michaela; Sadlonova, V.; Dokus, Karol; Adamkov, Marián; Ľupták, J.; Fraňová, Soňa

doi:10.1111/jog.12626

Cited by 2 publications

(3 citation statements)

References 28 publications

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“…The inconsistency may be attributable to the different experimental models in that the biphasic effect of 2-APB was observed against a non-uterine myocyte cell in monoculture using patch-clamp analysis, whereas our study utilized strips of pregnant human myometrium in a contraction bioassay system [ 15 , 58 , 59 ]. In support of this, existing literature demonstrates that isoform expression of STIM (1–2), a SR membrane protein that induces the opening of the SOCs, and ORAI (1–3), a plasma membrane protein that forms the pore of SOCs, differs between myometrial cells in culture and myometrial tissue [ 60 – 62 ]. 2-APB is shown to have differential effects on different STIM and ORAI isoforms [ 63 , 64 ], which together mediate SOCE.…”

Section: Discussionmentioning

confidence: 87%

Assessing the Potency of the Novel Tocolytics 2-APB, Glycyl-H-1152, and HC-067047 in Pregnant Human Myometrium

et al. 2022

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The intracellular signaling pathways that regulate myometrial contractions can be targeted by drugs for tocolysis. The agents, 2-APB, glycyl-H-1152, and HC-067047, have been identified as inhibitors of uterine contractility and may have tocolytic potential. However, the contraction-blocking potency of these novel tocolytics was yet to be comprehensively assessed and compared to agents that have seen greater scrutiny, such as the phosphodiesterase inhibitors, aminophylline and rolipram, or the clinically used tocolytics, nifedipine and indomethacin. We determined the IC50 concentrations (inhibit 50% of baseline contractility) for 2-APB, glycyl-H-1152, HC-067047, aminophylline, rolipram, nifedipine, and indomethacin against spontaneous ex vivo contractions in pregnant human myometrium, and then compared their tocolytic potency. Myometrial strips obtained from term, not-in-labor women, were treated with cumulative concentrations of the contraction-blocking agents. Comprehensive dose–response curves were generated. The IC50 concentrations were 53 µM for 2-APB, 18.2 µM for glycyl-H-1152, 48 µM for HC-067047, 318.5 µM for aminophylline, 4.3 µM for rolipram, 10 nM for nifedipine, and 59.5 µM for indomethacin. A single treatment with each drug at the determined IC50 concentration was confirmed to reduce contraction performance (AUC) by approximately 50%. Of the three novel tocolytics examined, glycyl-H-1152 was the most potent inhibitor. However, of all the drugs examined, the overall order of contraction-blocking potency in decreasing order was nifedipine > rolipram > glycyl-H-1152 > HC-067047 > 2-APB > indomethacin > aminophylline. These data provide greater insight into the contraction-blocking properties of some novel tocolytics, with glycyl-H-1152, in particular, emerging as a potential novel tocolytic for preventing preterm birth.

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Section: Discussionmentioning

confidence: 87%

Assessing the Potency of the Novel Tocolytics 2-APB, Glycyl-H-1152, and HC-067047 in Pregnant Human Myometrium

et al. 2022

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“…16 The presence of these proteins in uterine muscle cells has already been described: Orai1 in rat uterus, 17 Orai1/2/3, STIM1/2, and TRPC3 in pregnant and nonpregnant human myometrium. 18,20,21 Also described in derived cell lines of human myometrium, are TRPCs, Orai, and STIM. 19,20,22,23,[34][35][36] Our results in rat myometrium also indicated that Orai1 channels participate in the maintenance of muscarinic agonist-induced action.…”

Section: Discussionmentioning

confidence: 99%

“…16 Recently, the expression of STIM1 and Orai1 proteins in both human and rat myometrium has been reported. 17,18 The expression of these proteins, as well as STIM2 and Orai2/3 isoforms, have also been described in cultured myometrial human cells, such as isolated myometrial cells of both pregnant and nonpregnant women. 19,20 Furthermore, other channels that are considered SOC channels in other types of cells, such as transient receptor potential canonical (TRPC) 1/3/4/6 channels, are also detected in human myometrial cells.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of Pyr6 (an Orai channel blocker) on agonist‐induced contractions in rat uterus

Sousa

Meneses

Cardoso

et al. 2021

J of Obstet and Gynaecol

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Aim: Both human and rat myometrium express stromal interaction molecule (STIM) and Orai/transient receptor potential canonical (TRPC) proteins, which are components of plasma membrane Ca 2+ store-operated channels. There are reports that these proteins mediate agonist-induced Ca 2+ influx in cultured myometrial cells. In this study, we aimed to determine the effects of Pyr6, an Orai channel blocker, on different agonist-induced contractions in isolated segments of rat uterus. Main findings: In Ca 2+ -free Tyrode's solution, Pyr6 (3 μM) promoted a reduction in both the magnitude and frequency of Ca 2+ (1 mM)-induced uterine contractions after the addition of carbachol (CCh, 100 μM), but not after the addition of oxytocin (OT, 150 nM). In Ca 2+ (0.18 mM)-Tyrode's solution, Pyr6 completely relaxed uterine contractions induced by both CCh and cloprostenol (300 nM), but not those induced by either KCI (40-80 mM) or OT. The addition of Pyr6 abolished the oscillatory uterine contractions induced by Ca 2+ after the addition of cyclopiazonic acid (CPA, 10 μM). When pre-incubated (5 min), Pyr6 reduced the magnitude of both CCh-induced phasic and tonic contractions. The addition of Pyr2 (3 μM), an Orai and TRPC channel blocker, abolished uterine contractions induced by CCh or OT. Conclusion: Considering Pyr6 as an Orai channel blocker and its inhibitory effect on uterine contractions induced by CCh, CPA, and cloprostenol, we suggest that Orai channels are required for the maintenance of contractions induced by these agonists in rat uterus.

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Orai1 protein expression and the role of calcium release‐activated calcium channels in the contraction of human term‐pregnant and non‐pregnant myometrium

Abstract: Our results provide the first information about the changes in the Orai1 protein expression and activity of human myometrial CRAC channels in term-pregnant laboring myometrium.

Cited by 2 publications

References 28 publications

Assessing the Potency of the Novel Tocolytics 2-APB, Glycyl-H-1152, and HC-067047 in Pregnant Human Myometrium

Assessing the Potency of the Novel Tocolytics 2-APB, Glycyl-H-1152, and HC-067047 in Pregnant Human Myometrium

Inhibitory effect of Pyr6 (an Orai channel blocker) on agonist‐induced contractions in rat uterus

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