TRPM7 is a molecular substrate of ATP-evoked P2X7-like currents in tumor cells

Nörenberg, Wolfgang; Plötz, Tanja; Sobottka, Helga; Chubanov, Vladimir; Mittermeier, Lorenz; Aigner, Achim; Schaefer, Michael

doi:10.1085/jgp.201611595

Cited by 16 publications

(16 citation statements)

References 45 publications

(53 reference statements)

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“…Non-transfected HEK293T cells exhibit small outwardly rectifying currents in physiological calcium conditions, which become larger and ohmic (linear) in divalent free conditions. These intrinsic currents are largely attributed to native chloride and non-selective cationic TRPM7 channels in these cells (Nörenberg et al, 2016). …”

Section: Methodsmentioning

confidence: 99%

The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs

Shen

Yang

DeCaen

et al. 2016

Cell

223

352

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SUMMARY The Polycystic Kidney Disease 2 (pkd2) gene is mutated in autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic disorders. Here, we present the cryo-EM structure of PKD2 in lipid bilayers at 3.0 Å resolution, which establishes PKD2 as a homotetrameric ion channel and provides insight into potential mechanisms for its activation. The PKD2 voltage-sensor domain retains two of four gating charges commonly found in those of voltage-gated ion channels. The PKD2 ion permeation pathway is constricted at the selectivity filter and near the cytoplasmic end of S6, suggesting that two gates regulate ion conduction. The extracellular domain of PKD2, a hotspot for ADPKD pathogenic mutations, contributes to channel assembly and strategically interacts with the transmembrane core, likely serving as a physical substrate for extracellular stimuli to allosterically gate the channel. Finally, our structure establishes the molecular basis for the majority of pathogenic mutations in pkd2-related ADPKD.

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Section: Methodsmentioning

confidence: 99%

The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs

Shen

Yang

DeCaen

et al. 2016

Cell

223

352

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“…Cells were maintained in a humidified cell culture incubator (Heraeus, Thermo Fisher Scientific) at 37°C and 5% CO 2 . Western blot analysis was performed as described previously (Nörenberg et al, 2016). Examinations of growth rates and endogenous TRPM7-like currents were conducted as described above for TS cells.…”

Section: Methodsmentioning

confidence: 99%

Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival

Chubanov

Ferioli

Wisnowsky

et al. 2016

eLife

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104

116

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Mg2+ regulates many physiological processes and signalling pathways. However, little is known about the mechanisms underlying the organismal balance of Mg2+. Capitalizing on a set of newly generated mouse models, we provide an integrated mechanistic model of the regulation of organismal Mg2+ balance during prenatal development and in adult mice by the ion channel TRPM6. We show that TRPM6 activity in the placenta and yolk sac is essential for embryonic development. In adult mice, TRPM6 is required in the intestine to maintain organismal Mg2+ balance, but is dispensable in the kidney. Trpm6 inactivation in adult mice leads to a shortened lifespan, growth deficit and metabolic alterations indicative of impaired energy balance. Dietary Mg2+ supplementation not only rescues all phenotypes displayed by Trpm6-deficient adult mice, but also may extend the lifespan of wildtype mice. Hence, maintenance of organismal Mg2+ balance by TRPM6 is crucial for prenatal development and survival to adulthood.DOI: http://dx.doi.org/10.7554/eLife.20914.001

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“…Initially, agents acting as unspecific channel inhibitors, such as spermine [ 20 ], ruthenium red [ 81 ], trivalent cations [ 82 ], SKF-96365 [ 20 ] and 2-aminoethyl diphenylborinate (2-APB) [ 83 ], were used to block the TRPM7 channel. Subsequently, several drug-like molecules were reported as inhibitors of the TRPM7 channel effective only in a high µM range, such as nafamostat [ 84 ], carvacrol [ 85 , 86 , 87 , 88 , 89 ], 5-lipoxygenase inhibitors (NDGA, AA861 and MK886) [ 90 , 91 , 92 , 93 ], midazolam [ 94 , 95 ], ginsenoside Rg3 [ 96 ], ginsenoside-Rd [ 97 , 98 ], aripiprazole [ 99 ] and coomassie brilliant blue G-250 (BBG) [ 100 ]. Our laboratory identified several additional inhibitors of the TRPM7 channel such as quinine, CyPPA, dequalinium, SKA31, and UCL1684 [ 101 ].…”

Section: Drug-like Modulators the Channel And Kinase Activity Of Tmentioning

confidence: 99%

“…Nörenberg et al [ 100 ] used NS8593 to show that TRPM7 regulates ATP-induced currents, which were previously thought to be conducted by the P2X7 channel. P2X7 mediates nonselective cation currents that are typically elicited by high concentrations of extracellular ATP.…”

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

confidence: 99%

“…P2X7 mediates nonselective cation currents that are typically elicited by high concentrations of extracellular ATP. Nörenberg et al [ 100 ] re-examined such ATP-induced currents in HEK293 and rat glioma C6 cells and concluded that TRPM7 is the correct molecular correlate of ATP-induced currents. In another study, Sadowska et al employed NS8593 to rule out the involvement of TRPM7 in Ca 2+ -dependent osmosensing of nucleus pulposus cells [ 125 ].…”

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

confidence: 99%

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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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TRPM7 is a molecular substrate of ATP-evoked P2X7-like currents in tumor cells

Cited by 16 publications

References 45 publications

The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs

The Structure of the Polycystic Kidney Disease Channel PKD2 in Lipid Nanodiscs

Epithelial magnesium transport by TRPM6 is essential for prenatal development and adult survival

Mapping TRPM7 Function by NS8593

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