ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense

Grimes, Derayvia; Johnson, Ryan; Pashos, Madeline; Cummings, Celeste; Chen, Kang; Sampedro, Georgia R.; Tycksen, Eric; McBride, Helen J.; Sah, Rajan; Lowell, Clifford A.; Clemens, Regina A.

doi:10.1073/pnas.2008032117

Cited by 36 publications

(35 citation statements)

References 56 publications

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“…This phenomenon is probably mediated because Orai2 and Orai3 have a greater sensitivity to Ca 2+ -dependent inactivation than Orai1 [ 10 , 11 ]. By contrast, Orai2 has been reported to support SOCE in different cell types, such as HL-60 acute myeloid leukemia cells [ 12 ], bone marrow neutrophils [ 13 ] and gastric cancer cells [ 14 ]. Unlike Orai3, Orai1 and Orai2 share some biochemical features such as their sensitivity to pH, so that Orai1 and Orai2 currents are inhibited by acidification and enhanced by alkalization, while those of Orai3 are unaffected [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Orai2 Modulates Store-Operated Ca2+ Entry and Cell Cycle Progression in Breast Cancer Cells

Sánchez-Collado

López

Cantonero

et al. 2021

Cancers

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Breast cancer is a heterogeneous disease from the histological and molecular expression point of view, and this heterogeneity determines cancer aggressiveness. Store-operated Ca2+ entry (SOCE), a major mechanism for Ca2+ entry in non-excitable cells, is significantly remodeled in cancer cells and plays an important role in the development and support of different cancer hallmarks. The store-operated CRAC (Ca2+ release-activated Ca2+) channels are predominantly comprised of Orai1 but the participation of Orai2 and Orai3 subunits has been reported to modulate the magnitude of Ca2+ responses. Here we provide evidence for a heterogeneous expression of Orai2 among different breast cancer cell lines. In the HER2 and triple negative breast cancer cell lines SKBR3 and BT20, respectively, where the expression of Orai2 was greater, Orai2 modulates the magnitude of SOCE and sustain Ca2+ oscillations in response to carbachol. Interestingly, in these cells Orai2 modulates the activation of NFAT1 and NFAT4 in response to high and low agonist concentrations. Finally, we have found that, in cells with high Orai2 expression, Orai2 knockdown leads to cell cycle arrest at the G0-G1 phase and decreases apoptosis resistance upon cisplatin treatment. Altogether, these findings indicate that, in breast cancer cells with a high Orai2 expression, Orai2 plays a relevant functional role in agonist-evoked Ca2+ signals, cell proliferation and apoptosis resistance.

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Section: Introductionmentioning

confidence: 99%

Orai2 Modulates Store-Operated Ca2+ Entry and Cell Cycle Progression in Breast Cancer Cells

Sánchez-Collado

López

Cantonero

et al. 2021

Cancers

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“…For example, it was suggested that ORAI2 could participate in the formation of functional channels. Nonetheless, it was also highlighted that ORAI1 was present in the model studied [ 12 , 39 , 40 ]. In addition, Alansary et al [ 37 ] suggested that ORAI3 was responsible for a limited SOCE in HEK-293 cells KO for ORAI1 and ORAI2.…”

Section: Discussionmentioning

confidence: 99%

Impact of SOCE Abolition by ORAI1 Knockout on the Proliferation, Adhesion, and Migration of HEK-293 Cells

Bokhobza¹,

Ziental-Gelus²,

Allart³

et al. 2021

Cells

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Store-operated calcium entry (SOCE) provided through channels formed by ORAI proteins is a major regulator of several cellular processes. In immune cells, it controls fundamental processes such as proliferation, cell adhesion, and migration, while in cancer, SOCE and ORAI1 gene expression are dysregulated and lead to abnormal migration and/or cell proliferation. In the present study, we used the CRISPR/Cas9 technique to delete the ORAI1 gene and to identify its role in proliferative and migrative properties of the model cell line HEK-293. We showed that ORAI1 deletion greatly reduced SOCE. Thereby, we found that this decrease and the absence of ORAI1 protein did not affect HEK-293 proliferation. In addition, we determined that ORAI1 suppression did not affect adhesive properties but had a limited impact on HEK-293 migration. Overall, we showed that ORAI1 and SOCE are largely dispensable for cellular proliferation, migration, and cellular adhesion of HEK-293 cells. Thus, despite its importance in providing Ca2+ entry in non-excitable cells, our results indicate that the lack of SOCE does not deeply impact HEK-293 cells. This finding suggests the existence of compensatory mechanism enabling the maintenance of their physiological function.

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“… Numaga-Tomita and Putney, 2013 also found the knockdown of either STIM1 or ORAI1 to strongly suppress SOCE, causing impaired expression of keratin1, an early keratinocytes differentiation marker, and the inhibition of normal growth of HaCaT cells in low Ca 2+ . Additionally, decreased SOCE in ORAI1-, ORAI2-, and ORAI1/2-deficient immune cells, such as neutrophils, impairs multiple cellular functions, including phagocytosis, degranulation, leukotriene expression, and reactive oxygen species (ROS) production ( Grimes et al, 2020 ). Similarly, ORAI1 and ORAI2 can form a heteromorphic channel complex, in which ORAI2 attenuates the function of ORAI1 and limits SOCE, while ORAI2 fine-tunes the magnitude of SOCE to modulate immune responses ( Vaeth et al, 2017 ).…”

Section: Calcium-sensing Receptors and Channels Mediated Ca 2+ Signaling In Skin Function Maintenancementioning

confidence: 99%

Calcium Channels: Noteworthy Regulators and Therapeutic Targets in Dermatological Diseases

Wang

et al. 2021

Front. Pharmacol.

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Dysfunctional skin barrier and impaired skin homeostasis may lead to or aggravate a series of dermatologic diseases. A large variety of biological events and bioactive molecules are involved in the process of skin wound healing and functional recovery. Calcium ions (Ca2+) released from intracellular stores as well as influx through plasma membrane are essential to skin function. Growing evidence suggests that calcium influx is mainly regulated by calcium-sensing receptors and channels, including voltage-gated, transient potential receptor, store-operated, and receptor-operated calcium channels, which not only maintain cellular Ca2+ homeostasis, but also participate in cell proliferation and skin cell homeostasis through Ca2+-sensitive proteins such as calmodulin (CaM). Furthermore, distinct types of Ca2+ channels not merely work separately, they may work concertedly to regulate cell function. In this review, we discussed different calcium-sensing receptors and channels, including voltage-gated, transient receptor potential, store-operated, and receptor-operated calcium channels, particularly focusing on their regulatory functions and inherent interactions as well as calcium channels-related reagents and drugs, which is expected to bridge basic research and clinical applications in dermatologic diseases.

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ORAI1 and ORAI2 modulate murine neutrophil calcium signaling, cellular activation, and host defense

Cited by 36 publications

References 56 publications

Orai2 Modulates Store-Operated Ca2+ Entry and Cell Cycle Progression in Breast Cancer Cells

Orai2 Modulates Store-Operated Ca2+ Entry and Cell Cycle Progression in Breast Cancer Cells

Impact of SOCE Abolition by ORAI1 Knockout on the Proliferation, Adhesion, and Migration of HEK-293 Cells

Calcium Channels: Noteworthy Regulators and Therapeutic Targets in Dermatological Diseases

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