Cleavage of TRPM7 Releases the Kinase Domain from the Ion Channel and Regulates Its Participation in Fas-Induced Apoptosis

Desai, Bimal N.; Krapivinsky, Grigory; Navarro, Betsy; Krapivinsky, Luba; Carter, Brett C.; Febvay, Sébastien; Delling, Markus; Penumaka, Anirudh; Ramsey, I. Scott; Manasian, Yunona; Clapham, David E.

doi:10.1016/j.devcel.2012.04.006

Cited by 136 publications

(146 citation statements)

References 51 publications

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“…*P < 0.05, **P < 0.01. cellular differentiation. We showed recently that TRPM7 C-terminal kinase is cleaved from the channel in LN-18 cells undergoing Fas-induced apoptosis, and this cleavage induced an increase in TRPM7 channel activity that is required for apoptosis (38). Indeed, cleaved TRPM7 C-terminal kinase has been observed in other cell types (38), potentially freeing it to interact with cellular partners beyond the plasma membrane to modify transcriptional programs.…”

Section: Hcn4-creert2mentioning

confidence: 99%

Ion channel-kinase TRPM 7 is required for maintaining cardiac automaticity

Sah

Mesirca

Boogert

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

105

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Significance T ransient R eceptor P otential M elastatin 7 (TRPM7) is a divalent-permeant channel-kinase of unknown function expressed in human atrial myocytes and fibroblasts and recently implicated in atrial arrhythmias. We show that TRPM7 is highly expressed in embryonic myocardium and sinoatrial node (SAN). Trpm7 disruption in vitro, in cultured embryonic cardiomyocytes, and in vivo in zebrafish and in mice impairs cardiac automaticity. We show that this occurs via reductions in Hcn4 mRNA and the pacemaker current, I f , in SAN. We conclude that TRPM7 influences diastolic membrane depolarization and automaticity in SAN via regulation of Hcn4 expression.

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Section: Hcn4-creert2mentioning

confidence: 99%

Ion channel-kinase TRPM 7 is required for maintaining cardiac automaticity

Sah

Mesirca

Boogert

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

105

View full text Add to dashboard Cite

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“…Mice with inducible, T cell restricted TRPM7 deletion show a block in thymocyte development at the double negative stage and a depletion of thymic medullary cells, but no measureable changes in intracellular Ca 2+ or Mg 2+ concentrations ([7], reviewed in [6, 28]). However, in another study the same research group excluded any role for TRPM7 kinase in Fas induced apoptosis in TRPM7 -/- T-cells ([29], reviewed in [28]). Future studies will need to clarify whether this developmental phenotype is T cell specific, or if TRPM7 is such an essential gene that its absence is causing decreased viability and developmental failures in any cellular context.…”

Section: Introductionmentioning

confidence: 99%

TRPM6 kinase activity regulates TRPM7 trafficking and inhibits cellular growth under hypomagnesic conditions

Brandao

Deason-Towne

Zhao

et al. 2014

Cell. Mol. Life Sci.

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The channel kinases TRPM6 and TRPM7 are both members of the melastatin related transient receptor potential (TRPM) subfamily of ion channels and the only known fusions of an ion channel pore with a kinase domain. TRPM6 and TRPM7 form functional, tetrameric channel complexes at the plasma membrane by heteromerization. TRPM6 was previously shown to cross-phosphorylate TRPM7 on threonine residues, but not vice versa. Genetic studies demonstrated that TRPM6 and TRPM7 fulfill non-redundant functions, and that each channel contributes uniquely to the regulation of Mg2+ homeostasis. Although there are indications that TRPM6 and TRPM7 can influence each other’s cellular distribution and activity, little is known about the functional relationship between these two channel-kinases. In the present study, we examined how TRPM6 kinase activity influences TRPM7 serine phosphorylation, intracellular trafficking, and cell surface expression of TRPM7, as well as Mg2+-dependent cellular growth. We found TRPM7 serine phosphorylation via the TRPM6 kinase, but no TRPM6 serine phosphorylation via the TRPM7 kinase. Intracellular trafficking of TRPM7 was altered in HEK-293 epithelial kidney cells and DT40 B cells in the presence of TRPM6 with intact kinase activity, independently of the availability of extracellular Mg2+, but TRPM6/7 surface labeling experiments indicate comparable levels of the TRPM6/7 channels at the plasma membrane. Furthermore, using a complementation approach in TRPM7-deficient DT40 B-cells, we demonstrated that wildtype TRPM6 inhibited cell growth under hypomagnesic cell culture conditions in cells co-expressing TRPM6 and TRPM7, however co-expression of a TRPM6 kinase dead mutant had no effect – a similar phenotype was also observed in TRPM6/7 co-expressing HEK-293 cells. Our results provide first clues about how heteromer formation between TRPM6 and TRPM7 influences the biological activity of these ion channels. We show that TRPM6 regulates TRPM7 intracellular trafficking and TRPM7 dependent cell growth. All these effects are dependent upon the presence of an active TRPM6 kinase domain. Dysregulated Mg2+-homeostasis causes or exacerbates many pathologies. As TRPM6 and TRPM7 are expressed simultaneously in numerous cell types, understanding how their relationship impacts regulation of Mg2+-uptake is thus important knowledge.

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“…However, as we have shown, Trpm7 −/− cells have normal total magnesium concentrations (3,14), with the many abundant magnesium transporters (20) probably accounting for normal Mg 2+ homeostasis. Under physiological conditions, plasma membrane TRPM7's inward conductance is miniscule (<10 pA/pF at −100 mV), but it increases over minutes if the free cytosolic Mg 2+ concentration falls below its normal level of ∼0.5-1 mM (21).…”

mentioning

confidence: 99%

“…As an ion channel, TRPM7 conducts Zn 2+ >Mg 2+ ∼ Ca 2+ and monovalent cations (7-10) and contributes to labile cytosolic and nuclear Zn 2+ concentrations (8). TRPM7's C-terminal kinase can phosphorylate multiple substrates (11-13) and is cleaved to release a proapoptotic, chromatin-modifying enzyme (8,14). Zn 2+ regulates TRPM7's kinase activity (11) and binding to transcription factors (8).…”

mentioning

confidence: 99%

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles

Abiria

Krapivinsky

Sah

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

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TRPM7 (transient receptor potential cation channel subfamily M member 7) regulates gene expression and stress-induced cytotoxicity and is required in early embryogenesis through organ development. Here, we show that the majority of TRPM7 is localized in abundant intracellular vesicles. These vesicles (M7Vs) are distinct from endosomes, lysosomes, and other familiar vesicles or organelles. , an ion channel and cytoplasmic kinase, is ubiquitously expressed and essential in early embryonic development (1-4) but also may mediate oxidative stress-induced anoxic neuronal death in adults (5, 6). As an ion channel, TRPM7 conducts Zn 2+ >Mg 2+ ∼ Ca 2+ and monovalent cations (7-10) and contributes to labile cytosolic and nuclear Zn 2+ concentrations (8). TRPM7's C-terminal kinase can phosphorylate multiple substrates (11-13) and is cleaved to release a proapoptotic, chromatin-modifying enzyme (8,14). Zn 2+ regulates TRPM7's kinase activity (11) and binding to transcription factors (8). It is a potent signal for many cellular processes previously related to TRPM7 function, including gene expression, mitosis, and cell survival, but is also proapoptotic at extreme concentrations (15)(16)(17)(18) Oxidative stress increases inward divalent ion permeation through TRPM7 (5, 9), whereas acute and chronic oxidative stress in culture (24-26) or during ischemia-reperfusion in vivo (27, 28) induces TRPM7 expression. The resulting increase in cytosolic Zn 2+ could result in toxic cytosolic concentrations (9). Conversely, reduction of TRPM7 expression protects animals from postischemia reperfusion (5), a condition typically accompanied by increased reactive oxygen species (ROS) and Zn 2+ release from intracellular stores (29). Physiological redox transitions required for stem cell differentiation and gene expression during embryonic development (30, 31) may also be sensed by TRPM7 and transduced via Zn -dependent signals (32). Because TRPM7 patch-clamp recording is limited to the plasma membrane, the assumption has been that TRPM7's main function is on the plasma membrane. However, we have previously shown that TRPM7 is also on intracellular membranes (33-35). Indeed, ROS activation of divalent ion influx through TRPM7 (5, 9) is reminiscent of ROS activation of TRPM2, which releases Ca 2+ and Zn 2+ from lysosomes (36,37 ] and ROS during development and injury.

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Cleavage of TRPM7 Releases the Kinase Domain from the Ion Channel and Regulates Its Participation in Fas-Induced Apoptosis

Cited by 136 publications

References 51 publications

Ion channel-kinase TRPM 7 is required for maintaining cardiac automaticity

Ion channel-kinase TRPM 7 is required for maintaining cardiac automaticity

TRPM6 kinase activity regulates TRPM7 trafficking and inhibits cellular growth under hypomagnesic conditions

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles

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Cleavage of TRPM7 Releases the Kinase Domain from the Ion Channel and Regulates Its Participation in Fas-Induced Apoptosis

Cited by 136 publications

References 51 publications

Ion channel-kinase TRPM 7 is required for maintaining cardiac automaticity

Ion channel-kinase TRPM 7 is required for maintaining cardiac automaticity

TRPM6 kinase activity regulates TRPM7 trafficking and inhibits cellular growth under hypomagnesic conditions

TRPM7 senses oxidative stress to release Zn 2+ from unique intracellular vesicles

Contact Info

Product

Resources

About

TRPM7 senses oxidative stress to release Zn ²⁺ from unique intracellular vesicles