Role of Calcium Signaling in B Cell Activation and Biology

Baba, Yoshifumi; Kurosaki, Tomohiro

doi:10.1007/82_2015_477

Cited by 51 publications

(54 citation statements)

References 208 publications

(202 reference statements)

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“…). Ca 2+ signalling in B cells is fundamentally important for the development of adaptive immunity (Baba & Kurosaki, ). The apparent dependence of SOCE on functional TRPM7 kinase activity may represent a feedback loop for B‐cell receptor induced Ca 2+ signalling that is in relation to the availability of intracellular Mg·ATP for the cell.…”

Section: Discussionmentioning

confidence: 99%

The TRPM7 channel kinase regulates store‐operated calcium entry

Faouzi

Kilch

Horgen

et al. 2017

The Journal of Physiology

105

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The transient receptor potential melastatin 7 (TRPM7) is a protein that combines an ion channel with an intrinsic kinase domain, enabling it to modulate cellular functions either by conducting ions through the pore or by phosphorylating downstream proteins via its kinase domain. In the present study, we report store-operated calcium entry (SOCE) as a novel target of TRPM7 kinase activity. TRPM7-deficient chicken DT40 B lymphocytes exhibit a strongly impaired SOCE compared to wild-type cells as a result of reduced calcium release activated calcium currents, and independently of potassium channel regulation, membrane potential changes or changes in cell-cycle distribution. Pharmacological blockade of TRPM7 with NS8593 or waixenicin A in wild-type B lymphocytes results in a significant decrease in SOCE, confirming that TRPM7 activity is acutely linked to SOCE, without TRPM7 representing a store-operated channel itself. Using kinase-deficient mutants, we find that TRPM7 regulates SOCE through its kinase domain. Furthermore, Ca influx through TRPM7 is essential for the maintenance of endoplasmic reticulum Ca concentration in resting cells, and for the refilling of Ca stores after a Ca signalling event. We conclude that the channel kinase TRPM7 and SOCE are synergistic mechanisms regulating intracellular Ca homeostasis.

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Section: Discussionmentioning

confidence: 99%

The TRPM7 channel kinase regulates store‐operated calcium entry

Faouzi

Kilch

Horgen

et al. 2017

The Journal of Physiology

105

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“…Strong activation of the BCR signals successful SH and therefore end of SH, whereas CSR is not halted by the BCR signal . Co‐IP could not be used in this study, since Ca 2+ signals play a major role in the effects of stimulation of the BCR , and the nanomolar Ca 2+ concentration in vivo can't be kept during extract preparation and protocols such as co‐IP. Therefore, extract preparations and in vitro protocols such as co‐IP either use a Ca 2+ chelator or use Ca 2+ to have a stable high Ca 2+ concentration.…”

Section: Resultsmentioning

confidence: 99%

ETS1 and PAX5 transcription factors recruit AID to Igh DNA

et al. 2018

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B lymphocytes optimize antibody responses by class switch recombination (CSR), which changes the expressed constant region exon of the immunoglobulin heavy chain (IgH), and by somatic hypermutation (SH) that introduces point mutations in the variable regions of the antibody genes. Activation-induced cytidine deaminase (AID) is the key mutagenic enzyme that initiates both these antibody diversification processes by deaminating cytosine to uracil. Here we asked the question if transcription factors can mediate the specific targeting of the antibody diversification by recruiting AID. We have recently reported that AID is together with the transcription factors E2A, PAX5 and IRF4 in a complex on key sequences of the Igh locus. Here we report that also ETS1 is together with AID in this complex on key sequences of the Igh locus in splenic B cells of mice. Furthermore, we show that both ETS1 and PAX5 can directly recruit AID to DNA sequences from the Igh locus with the specific binding site for the transcription factor. Taken together, our findings support the notion of a targeting mechanism for the selective diversification of antibody genes with limited genome wide mutagenesis by recruitment of AID by PAX5 and ETS1 in a transcription factor complex.

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“…The release causes oscillations of cytosolic calcium (300,301) and the activation of store-operated currents in the plasma membrane of the lymphocyte (302). The activation of B lymphocytes also depends on calcium signals (303). Interestingly, the particular dynamics of calcium, single transients, repetitive oscillations or sustained plateau, determines the type of transcriptional factor activated in both T and B lymphocytes (304)(305)(306).…”

Section: On the Origin Of Type 2 Diabetes Mellitusmentioning

confidence: 99%

“…Interestingly, the particular dynamics of calcium, single transients, repetitive oscillations or sustained plateau, determines the type of transcriptional factor activated in both T and B lymphocytes (304)(305)(306). The central role of the calcium signaling in the immune response is emphasized by the fact that a defective calcium response in either T or B lymphocytes causes immunosuppression (303,307).…”

Section: On the Origin Of Type 2 Diabetes Mellitusmentioning

confidence: 99%

Electrical Excitability of the Endoplasmic Reticulum Membrane Drives Electrical Bursting and the Pulsatile Secretion of Insulin in a Pancreatic Beta Cell Model

Gómez-Barriocanal¹

2018

Preprint

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Pancreatic β-cells secrete insulin, the hormone that controls glucose homeostasis in vertebrates. When activated by glucose, β-cells display a biphasic electrical response. An initial phase, in which the cell fires action potentials continuously, is followed by a phase with a characteristic firing pattern, known as electrical bursting, that consists on brief pulses of action potentials separated by intervals of rest. Electrical bursting is believed to mediate the pulsatile secretion of insulin. The electrical response of β-cells has been extensively studied at experimental and theoretical level. However, there is still no consensus on the cellular mechanisms that underlie each of the phases of the response. In this paper, I propose the hypothesis that the pattern of the plasma membrane (PM) response of stimulated β-cells is generated by the electrical activity of the endoplasmic reticulum (ER) membrane. In this hypothesis, the interaction of the two excitable membranes, PM and ER membrane, each operating at a different time scale, generates both, the initial continuous phase and the periodic bursting The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/249805 doi: bioRxiv preprint first posted online mimics the actual effect of the factors on the frequency of bursting. Finally, the model shows that a cell with a defective ER response behaves like a dysfunctional β-cell from individuals with type 2 diabetes mellitus, a result that suggests that the electrical malfunction of the ER membrane may represent one of the primary causes of type 2 diabetes. Dynamic analysis of the ER behavior has revealed that, depending on the transport rates of Ca 2+ in and out of the ER, the system has three possible dynamic states. They consist on the hyperpolarization of the ER membrane, periodic oscillations of the electric potential across the membrane, and the depolarization of the membrane. Each of these states determines a different functional program in the cell. The hyperpolarized state maintains the cell at rest, in a non-secreting state. Periodic oscillations of the ER membrane cause electrical bursting in the PM and the consequent pulsatile secretion of insulin. Finally, the depolarized state causes continuous firing and an acute secretory activity, the hyperactive conditions of the initial phase of the β-cell response to glucose. The dynamic states of the ER are also associated with different long-term effects. So, conditions that induce the hyperactive depolarized state in β-cells also potentiate apoptosis. The induction of the oscillatory state by glucose and neuro-endocrine factors seems to activate also cell proliferation. In extreme conditions though, such as the chronic treatment of T2DM with incretin analogs, the activation of the oscillatory state may lead to the appearance of cancer. The mathematical model presented here is an illustration of how, even in a extremely simplified system, the nonlinearity or excitability of the ER membrane can produce a repertoire of dynamic state...

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Role of Calcium Signaling in B Cell Activation and Biology

Cited by 51 publications

References 208 publications

The TRPM7 channel kinase regulates store‐operated calcium entry

The TRPM7 channel kinase regulates store‐operated calcium entry

ETS1 and PAX5 transcription factors recruit AID to Igh DNA

Electrical Excitability of the Endoplasmic Reticulum Membrane Drives Electrical Bursting and the Pulsatile Secretion of Insulin in a Pancreatic Beta Cell Model

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