Ca2+ signaling in T lymphocytes: the interplay of the endoplasmic reticulum, mitochondria, membrane potential, and CRAC channels on transcription factor activation

Yang, Pei‐Chi; Jafri, M. Saleet

doi:10.1016/j.heliyon.2020.e03526

Cited by 21 publications

(34 citation statements)

References 93 publications

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“…A theoretical study closely based on experimental observations in airway smooth muscle cells enlightened the primary role played by SOCE in the maintenance of agonist induced Ca 2+ entry (27). A similar, phenomenological description of SOCE was introduced in an extended model of Ca 2+ signaling and transcription factor activation in T-lymphocytes (28). In another recent study, Yoast et al (29) used mathematical modelling to back-up their experimental investigation of the relation between the precise composition of ORAI heteromultimers and global Ca 2+ signaling that differentially activates NFAT-mediated transcriptional responses.…”

Section: Introductionmentioning

confidence: 99%

Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by the Interplay Between ORAI1 and InsP3 Receptors

2021

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Ca2+ signaling plays an essential role in T cell activation, which is a key step to start an adaptive immune response. During the transition from a quiescent to a fully activated state, Ca2+ microdomains characterized by reduced spatial and temporal extents are observed in the junctions between the plasma membrane (PM) and the endoplasmic reticulum (ER). Such Ca2+ responses can also occur in response to T cell adhesion to other cells or extracellular matrix proteins in otherwise unstimulated T cells. These non-TCR/CD3-dependent Ca2+ microdomains rely on d-myo-inositol 1,4,5-trisphosphate (IP3) signaling and subsequent store operated Ca2+ entry (SOCE) via the ORAI/STIM system. The detailed molecular mechanism of adhesion-dependent Ca2+ microdomain formation remains to be fully elucidated. We used mathematical modeling to investigate the spatiotemporal characteristics of T cell Ca2+ microdomains and their molecular regulators. We developed a reaction-diffusion model using COMSOL Multiphysics to describe the evolution of cytosolic and ER Ca2+ concentrations in a three-dimensional ER-PM junction. Equations are based on a previously proposed realistic description of the junction, which is extended to take into account IP3 receptors (IP3R) that are located next to the junction. The first model only considered the ORAI channels and the SERCA pumps. Taking into account the existence of preformed clusters of ORAI1 and STIM2, ORAI1 slightly opens in conditions of a full ER. These simulated Ca2+ microdomains are too small as compared to those observed in unstimulated T cells. When considering the opening of the IP3Rs located near the junction, the local depletion of ER Ca2+ allows for larger Ca2+ fluxes through the ORAI1 channels and hence larger local Ca2+ concentrations. Computational results moreover show that Ca2+ diffusion in the ER has a major impact on the Ca2+ changes in the junction, by affecting the local Ca2+ gradients in the sub-PM ER. Besides pointing out the likely involvement of the spontaneous openings of IP3Rs in the activation of SOCE in conditions of T cell adhesion prior to full activation, the model provides a tool to investigate how Ca2+ microdomains extent and interact in response to T cell receptor activation.

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Section: Introductionmentioning

confidence: 99%

Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by the Interplay Between ORAI1 and InsP3 Receptors

2021

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“…Calcium signaling is of fundamental importance in the regulation of physiological events, such as activation, proliferation, and differentiation in a variety of immune cells, including T-lymphocytes [ 1 , 2 ]. Under resting state, the intracellular calcium concentration ([Ca 2+ ] i ) of T-lymphocytes is approximately 100 nM, which transiently elevates to 1 µM when surface receptors of T-cells are stimulated by the complexes of antigen and major histocompatibility complex; this triggers the activation state of phospholipase C-gamma, which subsequently cleaves phosphatidylinositol-4,5-bisphosphate into two signaling molecules, including inositol-1,4,5-trisphosphate (IP 3 ) [ 2 , 3 , 4 ]. The release of IP 3 results in rapid increases of ([Ca 2+ ] i ) from the endoplasmic reticulum (ER) and outside the cell [ 3 ].…”

Section: Introductionmentioning

confidence: 99%

Anti-Inflammatory Effect of Licochalcone A via Regulation of ORAI1 and K+ Channels in T-Lymphocytes

Hong

Kim

et al. 2021

IJMS

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Calcium signaling plays a vital role in the regulation of various cellular processes, including activation, proliferation, and differentiation of T-lymphocytes, which is mediated by ORAI1 and potassium (K+) channels. These channels have also been identified as highly attractive therapeutic targets for immune-related diseases. Licochalcone A is a licorice-derived chalconoid known for its multifaceted beneficial effects in pharmacological treatments, including its anti-inflammatory, anti-asthmatic, antioxidant, antimicrobial, and antitumorigenic properties. However, its anti-inflammatory effects involving ion channels in lymphocytes remain unclear. Thus, the present study aimed to investigate whether licochalcone A inhibits ORAI1 and K+ channels in T-lymphocytes. Our results indicated that licochalcone A suppressed all three channels (ORAI1, Kv1.3, and KCa3.1) in a concentration-dependent matter, with IC50 values of 2.97 ± 1.217 µM, 0.83 ± 1.222 µM, and 11.21 ± 1.07 µM, respectively. Of note, licochalcone A exerted its suppressive effects on the IL-2 secretion and proliferation in CD3 and CD28 antibody-induced T-cells. These results indicate that the use of licochalcone A may provide an effective treatment strategy for inflammation-related immune diseases.

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“…T cell receptor engagement leads to the depletion of Ca 2+ stores within the ER and the phosphorylation of PLCγ (Yang and Jafri, 2020). Although two isoforms of PLCγ have been described, namely PLCγ1 and PLCγ2 (Joseph et al, 2014) T cells mainly express PLCγ1 (Joseph et al, 2014).…”

Section: Interaction Between Dendritic Cells and T Cellsmentioning

confidence: 99%

“…Although two isoforms of PLCγ have been described, namely PLCγ1 and PLCγ2 (Joseph et al, 2014) T cells mainly express PLCγ1 (Joseph et al, 2014). The activation of a tyrosine kinase promotes the PLCγ1 phosphorylation, and therein, its activation (Vaeth et al, 2020;Yang and Jafri, 2020). PLCγ1 hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP 2 ) into DAG and IP 3 , molecules that act as second messengers in these cells (Vaeth et al, 2020;Yang and Jafri, 2020).…”

Section: Interaction Between Dendritic Cells and T Cellsmentioning

confidence: 99%

Modulation of Adaptive Immunity and Viral Infections by Ion Channels

et al. 2021

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Most cellular functions require of ion homeostasis and ion movement. Among others, ion channels play a crucial role in controlling the homeostasis of anions and cations concentration between the extracellular and intracellular compartments. Calcium (Ca2+) is one of the most relevant ions involved in regulating critical functions of immune cells, allowing the appropriate development of immune cell responses against pathogens and tumor cells. Due to the importance of Ca2+ in inducing the immune response, some viruses have evolved mechanisms to modulate intracellular Ca2+ concentrations and the mobilization of this cation through Ca2+ channels to increase their infectivity and to evade the immune system using different mechanisms. For instance, some viral infections require the influx of Ca2+ through ionic channels as a first step to enter the cell, as well as their replication and budding. Moreover, through the expression of viral proteins on the surface of infected cells, Ca2+ channels function can be altered, enhancing the pathogen evasion of the adaptive immune response. In this article, we review those ion channels and ion transporters that are essential for the function of immune cells. Specifically, cation channels and Ca2+ channels in the context of viral infections and their contribution to the modulation of adaptive immune responses.

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Ca2+ signaling in T lymphocytes: the interplay of the endoplasmic reticulum, mitochondria, membrane potential, and CRAC channels on transcription factor activation

Cited by 21 publications

References 93 publications

Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by the Interplay Between ORAI1 and InsP3 Receptors

Three-Dimensional Model of Sub-Plasmalemmal Ca2+ Microdomains Evoked by the Interplay Between ORAI1 and InsP3 Receptors

Anti-Inflammatory Effect of Licochalcone A via Regulation of ORAI1 and K+ Channels in T-Lymphocytes

Modulation of Adaptive Immunity and Viral Infections by Ion Channels

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