The channel-kinase TRPM7 regulates antigen gathering and internalization in B cells

Krishnamoorthy, Mithunah; Wasim, Laabiah; Buhari, Fathima Hifza Mohamed; Zhao, Tiantian; Mahtani, Trisha; Ho, Jason; Kang, Sohee; Deason-Towne, Francina; Perraud, Anne‐Laure; Schmitz, C.; Treanor, Bebhinn

doi:10.1126/scisignal.aah6692

Cited by 18 publications

(23 citation statements)

References 56 publications

(94 reference statements)

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“…Krishnamoorthy et al [ 121 ] took advantage of NS8593 to demonstrate that TRPM7 controls antigen internalization and presentation in B cells. The DT40 B cell line deficient in the TRPM7 gene was unable to aggregate antigen after activation likely due to abnormal phospholipase C (isoform γ2) signalling and altered lipid metabolism.…”

Section: Ns8593 As a Tool To Investigate The Function Of Trpm7 Curmentioning

confidence: 99%

Mapping TRPM7 Function by NS8593

Chubanov¹,

Gudermann²

2020

IJMS

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The transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a ubiquitously expressed membrane protein, which forms a channel linked to a cytosolic protein kinase. Genetic inactivation of TRPM7 in animal models uncovered the critical role of TRPM7 in early embryonic development, immune responses, and the organismal balance of Zn2+, Mg2+, and Ca2+. TRPM7 emerged as a new therapeutic target because malfunctions of TRPM7 have been associated with anoxic neuronal death, tissue fibrosis, tumour progression, and giant platelet disorder. Recently, several laboratories have identified pharmacological compounds allowing to modulate either channel or kinase activity of TRPM7. Among other small molecules, NS8593 has been defined as a potent negative gating regulator of the TRPM7 channel. Consequently, several groups applied NS8593 to investigate cellular pathways regulated by TRPM7. Here, we summarize the progress in this research area. In particular, two notable milestones have been reached in the assessment of TRPM7 druggability. Firstly, several laboratories demonstrated that NS8593 treatment reliably mirrors prominent phenotypes of cells manipulated by genetic inactivation of TRPM7. Secondly, it has been shown that NS8593 allows us to probe the therapeutic potential of TRPM7 in animal models of human diseases. Collectively, these studies employing NS8593 may serve as a blueprint for the preclinical assessment of TRPM7-targeting drugs.

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Section: Ns8593 As a Tool To Investigate The Function Of Trpm7 Curmentioning

confidence: 99%

Mapping TRPM7 Function by NS8593

Chubanov¹,

Gudermann²

2020

IJMS

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“…Studies showing the effect of disturbances in Mg 2+ homeostasis on the mechanisms of differentiation, proliferation, and maturation of hematopoietic cells in the bone marrow are rare, and there are few references in recent decades about this topic, whereby the majority of the results were obtained only in experimental models [ 15 ]. These studies demonstrated the impact of Mg 2+ deficiency on peripheral blood cells [ 4 , 5 ] or on the lymphocyte maturation process, as well as on thrombopoiesis, with a focus on the transient receptor potential cation channel subfamily M member 7 (TRPM7) channel [ 16 , 17 ]. Several studies raised the importance of intracellular Mg 2+ homeostasis via the TRPM7 channel, which in addition to being permeable to Mg 2+ , is also permeable to Ca 2+ and Zn 2+ , relevant for processes such as growth, survival, differentiation, and cell migration [ 18 , 19 , 20 , 21 , 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

A Review of the Action of Magnesium on Several Processes Involved in the Modulation of Hematopoiesis

Lima

Fock

2020

IJMS

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Magnesium (Mg2+) is an essential mineral for the functioning and maintenance of the body. Disturbances in Mg2+ intracellular homeostasis result in cell-membrane modification, an increase in oxidative stress, alteration in the proliferation mechanism, differentiation, and apoptosis. Mg2+ deficiency often results in inflammation, with activation of inflammatory pathways and increased production of proinflammatory cytokines by immune cells. Immune cells and others that make up the blood system are from hematopoietic tissue in the bone marrow. The hematopoietic tissue is a tissue with high indices of renovation, and Mg2+ has a pivotal role in the cell replication process, as well as DNA and RNA synthesis. However, the impact of the intra- and extracellular disturbance of Mg2+ homeostasis on the hematopoietic tissue is little explored. This review deals specifically with the physiological requirements of Mg2+ on hematopoiesis, showing various studies related to the physiological requirements and the effects of deficiency or excess of this mineral on the hematopoiesis regulation, as well as on the specific process of erythropoiesis, granulopoiesis, lymphopoiesis, and thrombopoiesis. The literature selected includes studies in vitro, in animal models, and in humans, giving details about the impact that alterations of Mg2+ homeostasis can have on hematopoietic cells and hematopoietic tissue.

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“…We recently identified an important role for TRPM7 in regulating the actin cytoskeleton and consequently several early events in B‐cell activation . We demonstrated that deletion of TRPM7 in DT40 B cells led to cytoskeletal defects both at resting state and upon activation, as TRPM7‐KO B cells exhibited elongated filopodia‐like protrusions, but reduced lamellipodia when cells are adhered to glass.…”

Section: Ion Channels In Early B‐cell Activation and Synapse Formationmentioning

confidence: 91%

“…TRPM7 is a non‐selective cation channel that has been implicated in calcium influx and store recovery upon BCR stimulation, as well as Mg 2+ homeostasis . We recently identified a key role for both the channel and kinase functions of TRPM7 in BCR signaling and activation . We found that both TRPM7‐KO and kinase‐dead (KD) DT40 B cells have increased and sustained ERK phosphorylation upon BCR stimulation.…”

Section: Ion Channels In Bcr Activation and Signalingmentioning

confidence: 91%

Beyond the CRAC: Diversification of ion signaling in B cells

Mahtani

Treanor

2019

Immunological Reviews

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Ion channels act as critical gatekeepers, regulating the entry of ions such as sodium, calcium potassium, and magnesium into cells. While many are familiar with ion channels involved in the transport of calcium, and the important role of calcium as a second messenger in immune cell signaling, there are a multitude of ion channels, and together, they play a vital role in numerous metabolic and cellular processes. The importance of which is evidenced by the myriad of human disease pathologies associated with either ion deficiencies, or mutations in ion channel proteins, collectively referred to as channelopathies, and include both immunodeficiencies and autoimmune diseases. While the role of several ions and the interrogation of ion channels has been most extensively studied in the nervous system, we have also learned much about ion signaling and identified critical ion channels in T-cell biology; however, much less is known about ion signaling in B cells. Thus, this review is focused on the key role ions and ion channels and transporters play Abstract Although calcium signaling and the important role of calcium release-activated calcium channels is well recognized in the context of immune cell signaling, there is a vast diversity of ion channels and transporters that regulate the entry of ions beyond calcium, including magnesium, zinc, potassium, sodium, and chloride. These ions play a critical role in numerous metabolic and cellular processes. The importance of ions in human health and disease is illustrated by the identification of primary immunodeficiencies in patients with mutations in genes encoding ion channels and transporters, as well as the immunological defects observed in individuals with nutritional ion deficiencies. Despite progress in identifying the important role of ions in immune cell development and activation, we are still in the early stages of exploring the diversity of ion channels and transporters and mechanistically understanding the role of these ions in immune cell biology. Here, we review the biology of ion signaling in B cells and the identification of critical ion channels and transporters in B-cell development, activation, and differentiation into effector cells. Elucidating the role of ion channels and transporters in immune cell signaling is critical for expanding the repertoire of potential therapeutics for the treatment of immune disorders. Moreover, increased understanding of the role of ions in immune cell function will enhance our understanding of the potentially serious consequences of ion deficiencies in human health and disease. K E Y W O R D S calcium, CRAC, ion channels, magnesium, TRP, zincThis is an open access article under the terms of the Creat ive Commo ns Attri bution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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The channel-kinase TRPM7 regulates antigen gathering and internalization in B cells

Cited by 18 publications

References 56 publications

Mapping TRPM7 Function by NS8593

Mapping TRPM7 Function by NS8593

A Review of the Action of Magnesium on Several Processes Involved in the Modulation of Hematopoiesis

Beyond the CRAC: Diversification of ion signaling in B cells

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