scholarly journals TRPM7 Upregulate the Activity of SMAD1 through PLC Signaling Way to Promote Osteogenesis of hBMSCs

2020 ◽  
Vol 2020 ◽  
pp. 1-23
Author(s):  
Fanfan Hong ◽  
Shali Wu ◽  
Cui Zhang ◽  
Liang Li ◽  
Jianling Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Essential Role ◽  
Potential Role ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Osteogenic Induction ◽  
Transient Receptor

TRPM7 is a member of the transient receptor potential cation channel (TRP channel) subfamily M and possesses both an ion channel domain and a functional serine/threonine α-kinase domain. It has been proven to play an essential role in the osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs). However, the signaling pathway and molecular mechanism for TRPM7 in regulating osteogenic differentiation remain largely unknown. In this study, the potential role and mechanism of TRPM7 in the osteogenic differentiation of hBMSCs were investigated. The results showed that the expression of TRPM7 mRNA and protein increased, as did the osteogenic induction time. Upregulation or inhibition of TRPM7 could promote or inhibit the osteogenic differentiation of hBMSCs for 14 days. It was also found that the upregulation or inhibition of TRPM7 promoted or inhibited the activity of PLC and SMAD1, respectively, during osteogenic differentiation. PLC could promote osteogenic differentiation by upregulating the activity of SMAD1. However, inhibition of PLC alone could reduce the activity of SMAD1 but not inhibit completely the activation of SMAD1. Therefore, we inferred that it is an important signaling pathway for TRPM7 to upregulate the activity of SMAD1 through PLC and thereby promote the osteogenic differentiation of hBMSCs, but it is not a singular pathway. TRPM7 may also regulate the activation of SMAD1 through other ways, except for PLC, during osteogenic differentiation of hBMSCs.

The TRPM7 Channel in the Nervous and Cardiovascular Systems

2020 ◽  
Vol 21 (10) ◽  
pp. 985-992 ◽  
Author(s):  
Koichi Inoue ◽  
Zhi-Gang Xiong ◽  
Takatoshi Ueki
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Cellular Functions ◽  
Transient Receptor Potential Melastatin ◽  
Cation Permeability ◽  
Cardiovascular Systems ◽  
Transient Receptor ◽  
Excitatory Responses ◽  
Dual Operations

: Transient receptor potential melastatin 7 (TRPM7), along with the closely related TRPM6, are unique channels that have dual operations: cation permeability and kinase activity. In contrast to the limited tissue distribution of TRPM6, TRPM7 is widely expressed among tissues and is therefore implicated in a variety of cellular functions physiologically and pathophysiologically. The discovery of TRPM7’s unique structure imparting dual ion channel and kinase activities shed light onto novel and peculiar biological functions, such as Mg2+ homeostasis, cellular Ca2+ flickering, and even intranuclear transcriptional regulation by a cleaved kinase domain translocated to nuclei. Interestingly, at a higher level, TRPM7 participates in several biological processes in the nervous and cardiovascular systems, in which excitatory responses in neurons and cardiomyocytes are critical for their function. Here, we review the roles of TRPM7 in cells involved in the nervous and cardiovascular systems and discuss its potential as a future therapeutic target.

Abstract 660: Macrophage Specific Deficiency of the Transient Receptor Potential Canonical 3 Channel Reduces Apoptosis and Necrosis in Advanced Atherosclerotic Plaques

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Sumeet A Solanki ◽  
Guillermo Vazquez
Keyword(s):  
Bone Marrow ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Atherosclerotic Plaques ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Transient Receptor Potential Canonical ◽  
Transient Receptor ◽  
Apoptosis And Necrosis

Background: Macrophage apoptosis plays a critical role in progression of atherosclerosis. Previous studies suggest that M1 and M2 macrophage phenotypes dominate atherosclerosis. Recently, we showed that advanced lesions in the aortic root of Apoe -/- mice transplanted with bone marrow deficient in the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and less apoptotic macrophages. However, the donor mice used in these studies had global deficiency of TRPC3, raising the question whether the observed phenotype was also contributed by TRPC3-deficient non-myeloid cells which could undermine the true impact of macrophage deletion of TRPC3. To address this important question, we generated mice with macrophage-specific loss of TRPC3 function (MacTrpc3 -/- ). Methods & results: 13 six week-old female Ldlr -/- mice were irradiated and transplanted with Ldlr -/- (control) or MacTrpc3 -/- Ldlr -/- (experimental) bone marrow and kept on high fat diet for 14 weeks. At the end of the diet period, aortic roots were sectioned and processed for atherosclerotic lesion analysis. Total lesion size (H&E), neutral lipid (Oil Red O) and macrophage content (CD68 staining) were not different between groups. However, we found a 1.7 fold decrease (P=0.01) in percent necrotic area in advanced lesions of MacTrpc3 -/- Ldlr -/- mice (23.12 ± 2.07%, n=10) compared to controls (39.63 ± 5.93%, n=10). Using in situ TUNEL we found that MacTrpc3 -/- Ldlr -/- lesions have less apoptotic cells compared to controls, and these overlapped with CD68 + areas. Using iNOS and mannose receptor as markers for M1 and M2 macrophages, respectively, we found that both subsets overlapped with CD68 + and TUNEL + positive areas, with no differences between groups (n=5). Previously, we showed that M1, but not M2 macrophages derived from MacTrpc3 -/- mice, had reduced apoptosis. This suggests that reduced plaque necrosis of MacTrpc3 -/- Ldlr -/- mice may be due to reduced apoptosis of M1 macrophages. In sum, these in vivo studies indicate that macrophage-specific deficiency of TRPC3 has a genuine beneficial effect on advanced atherosclerotic plaques, reducing apoptosis and necrosis, probably due to a selective effect of TRPC3 on M1 macrophages.

Abstract MP48: EGF Regulates VSMC Migration And Proliferation Through Crosstalk Between TRPM7 And EGFR

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Francisco J Rios ◽  
ZhiGuo Zou ◽  
Karla B Neves ◽  
Rheure Alves-lopes ◽  
Jiayue Ling ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Transient Receptor Potential ◽  
Egf Receptor ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Proximity Ligation Assay ◽  
Transient Receptor Potential Melastatin ◽  
Egfr Expression ◽  
Transient Receptor ◽  
Egf Signaling

Epidermal growth factor (EGF), signals throught the EGF receptor (EGFR) and plays an important role in the pathogenesis of vascular remodeling. Transient receptor potential melastatin 7 (TRPM7) is a channel bound to a kinase domain important for Mg 2+ , Zn 2+ and Ca 2+ homeostasis. Cancer patients treated with EGFR inhibitors develop hypomagnesemia, suggesting a relationship between EGFR and TRPM7. Here we investigated the role of TRPM7 in EGF signaling in vascular smooth muscle cell (VSMC) from humans (hVSMC) and rats (rVSMC). VSMCs were stimulated with EGF (50ng/ml) for 5min and 24h with/without pretreatment of gefitinib (1μM), PP2 (10μM), 2APB (30μM) and NS8593 (40μM), inhibitors of EGFR, c-Src kinase and TRPM7 respectively. Aortas were isolated from wild type (WT), TRPM7-deficient (TRPM7 +/Δkinase ) and kinase-dead (TRPM7 R/R ) mice. Protein expression was assessed by immunoblotting. Ca 2+ and Mg 2+ were assessed using Cal-520 and Mg-green probes respectively. EGFR/TRPM7 interaction was investigated by proximity ligation assay (PLA), immunoprecipitation and confocal microscopy. VSMC migration and proliferation were examined by wound healing and CFSE proliferation assays. In hVSMC and rVSMC, EGF increased TRPM7 expression (47%) and phosphorylation (21%), (p<0.05); effects abolished by gefitinib and PP2. EGF-induced Mg 2+ and Ca 2+ influx was attenuated by gefitinib (4% and 8% respectively), NS8593 (5% for Mg 2+ ) and 2-APB (6% and 13% respectively). EGF enhanced ERK1/2 phosphorylation (3-fold) through c-Src, EGFR and TRPM7, p<0.05. Cell migration (26%) and proliferation (17%) were enhanced by EGF, and reduced by inhibitors of EGFR, TRPM7 and ERK1/2, p<0.05. EGF induced TRPM7-EGFR interaction (51%), which was reduced by gefitinib (34%) and PP2 (25%). VSMC from TRPM7 +/Δkinase showed reduced EGFR expression (73%), phospho-c-Src (22%), and phospho-ERK1/2 (90%). Aortas from TRPM7 R/R exhibited reduced phospho-EGFR (63%) and phospho-ERK1/2 (36%). Vessels from TRPM7 +/Δkinase showed reduced wall thickness (35%). Our findings demonstrate that interaction between EGFR/TRPM7 is a key process underlying EGF-induced VSMC migration and growth. This novel EGF-c-Src-EGFR-TRPM7 pathway may play an important role in vascular remodeling.

scholarly journals Heat Avoidance Is Regulated by Transient Receptor Potential (TRP) Channels and a Neuropeptide Signaling Pathway inCaenorhabditis elegans

Genetics ◽  
2011 ◽  
Vol 188 (1) ◽  
pp. 91-103 ◽  
Author(s):  
Dominique A. Glauser ◽  
Will C. Chen ◽  
Rebecca Agin ◽  
Bronwyn L. MacInnis ◽  
Andrew B. Hellman ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Transient Receptor

scholarly journals Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

2017 ◽  
Vol 114 (34) ◽  
pp. E7092-E7100 ◽  
Author(s):  
Grigory Krapivinsky ◽  
Luba Krapivinsky ◽  
Nora E. Renthal ◽  
Ana Santa-Cruz ◽  
Yunona Manasian ◽  
...  
Keyword(s):  
Molecular Complex ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Kinase Domain ◽  
Arginine Methylation ◽  
Global Changes ◽  
Histone Phosphorylation ◽  
Arginine Residues ◽  
A Cell ◽  
Transient Receptor

TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating histone arginine residues. Histone phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in histone S/T phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific histone phosphorylation. M6CK histone phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.

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