scholarly journals TRPM7 residue S1269 mediates cAMP dependence of Ca2+ influx

2018 ◽  
Author(s):  
Jorrit Broertjes ◽  
Jeffrey Klarenbeek ◽  
Yasmin Habani ◽  
Michiel Langeslag ◽  
Kees Jalink
Keyword(s):  
Transient Receptor Potential ◽  
Cultured Cells ◽  
Mutational Analysis ◽  
Epithelial Mesenchymal Transition ◽  
Neuroblastoma Cells ◽  
Coiled Coil ◽  
Receptor Potential ◽  
Mesenchymal Transition ◽  
Transient Receptor Potential Melastatin ◽  
C Terminus

AbstractThe nonspecific divalent cation channel TRPM7 (transient receptor potential-melastatin-like 7) is involved in many Ca2+ and Mg2+-dependent cellular processes, including survival, proliferation and migration. TRPM7 expression predicts metastasis and recurrence in breast cancer and several other cancers. In cultured cells, it can induce an invasive phenotype by promoting Ca2+-mediated epithelial-mesenchymal transition. We previously showed that in neuroblastoma cells that overexpress TRPM7 moderately, stimulation with Ca2+-mobilizing agonists leads to a characteristic sustained influx of Ca2+. Here we report that sustained influx through TRPM7 is abruptly abrogated by elevating intracellular levels of cAMP. Using pharmacological inhibitors and overexpression studies we show that this blockage is mediated by the cAMP effector Protein Kinase A (PKA). Mutational analysis demonstrates that the Serine residue S1269, which is present proximal to the coiled-coil domain within the protein c-terminus, is responsible for sensitivity to cAMP.

scholarly journals TRPM Channels in Human Diseases

Cells ◽  
2020 ◽  
Vol 9 (12) ◽  
pp. 2604
Author(s):  
Ivanka Jimenez ◽  
Yolanda Prado ◽  
Felipe Marchant ◽  
Carolina Otero ◽  
Felipe Eltit ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Transmembrane Domain ◽  
Current Knowledge ◽  
Coiled Coil ◽  
Receptor Potential ◽  
Point Of View ◽  
Human Diseases ◽  
Diagnostic Strategies ◽  
Transient Receptor Potential Melastatin ◽  
C Terminus

The transient receptor potential melastatin (TRPM) subfamily belongs to the TRP cation channels family. Since the first cloning of TRPM1 in 1989, tremendous progress has been made in identifying novel members of the TRPM subfamily and their functions. The TRPM subfamily is composed of eight members consisting of four six-transmembrane domain subunits, resulting in homomeric or heteromeric channels. From a structural point of view, based on the homology sequence of the coiled-coil in the C-terminus, the eight TRPM members are clustered into four groups: TRPM1/M3, M2/M8, M4/M5 and M6/M7. TRPM subfamily members have been involved in several physiological functions. However, they are also linked to diverse pathophysiological human processes. Alterations in the expression and function of TRPM subfamily ion channels might generate several human diseases including cardiovascular and neurodegenerative alterations, organ dysfunction, cancer and many other channelopathies. These effects position them as remarkable putative targets for novel diagnostic strategies, drug design and therapeutic approaches. Here, we review the current knowledge about the main characteristics of all members of the TRPM family, focusing on their actions in human diseases.

scholarly journals Structure of full-length human TRPM4

2018 ◽  
Vol 115 (10) ◽  
pp. 2377-2382 ◽  
Author(s):  
Jingjing Duan ◽  
Zongli Li ◽  
Jian Li ◽  
Ana Santa-Cruz ◽  
Silvia Sanchez-Martinez ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Trp Channels ◽  
Coiled Coil ◽  
Receptor Potential ◽  
Lipid Binding ◽  
Full Length ◽  
Intramolecular Interactions ◽  
Coiled Coil Domain ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Transient receptor potential melastatin subfamily member 4 (TRPM4) is a widely distributed, calcium-activated, monovalent-selective cation channel. Mutations in human TRPM4 (hTRPM4) result in progressive familial heart block. Here, we report the electron cryomicroscopy structure of hTRPM4 in a closed, Na+-bound, apo state at pH 7.5 to an overall resolution of 3.7 Å. Five partially hydrated sodium ions are proposed to occupy the center of the conduction pore and the entrance to the coiled-coil domain. We identify an upper gate in the selectivity filter and a lower gate at the entrance to the cytoplasmic coiled-coil domain. Intramolecular interactions exist between the TRP domain and the S4–S5 linker, N-terminal domain, and N and C termini. Finally, we identify aromatic interactions via π–π bonds and cation–π bonds, glycosylation at an N-linked extracellular site, a pore-loop disulfide bond, and 24 lipid binding sites. We compare and contrast this structure with other TRP channels and discuss potential mechanisms of regulation and gating of human full-length TRPM4.

scholarly journals Transient Receptor Potential Channel 6 Knockout Ameliorates Kidney Fibrosis by Inhibition of Epithelial–Mesenchymal Transition

2021 ◽  
Vol 8 ◽  
Author(s):  
Yanhong Zhang ◽  
Nina Yin ◽  
Anbang Sun ◽  
Qifang Wu ◽  
Wenzhu Hu ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Epithelial Mesenchymal Transition ◽  
Kidney Diseases ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Kidney Fibrosis ◽  
Mesenchymal Transition ◽  
Transient Receptor ◽  
End Stage ◽  
The Relationship

Kidney fibrosis is generally confirmed to have a significant role in chronic kidney disease, resulting in end-stage kidney failure. Epithelial–mesenchymal transition (EMT) is an important molecular mechanism contributing to fibrosis. Tubular epithelial cells (TEC), the major component of kidney parenchyma, are vulnerable to different types of injuries and are a significant source of myofibroblast by EMT. Furthermore, TRPC6 knockout plays an anti-fibrotic role in ameliorating kidney damage. However, the relationship between TRPC6 and EMT is unknown. In this study, TRPC6−/− and wild-type (WT) mice were subjected to a unilateral ureteric obstruction (UUO) operation. Primary TEC were treated with TGF-β1. Western blot and immunofluorescence data showed that fibrotic injuries alleviated with the inhibition of EMT in TRPC6−/− mice compared to WT mice. The activation of AKT-mTOR and ERK1/2 pathways was down-regulated in the TRPC6−/− mice, while the loss of Na+/K+-ATPase and APQ1 was partially recovered. We conclude that TRPC6 knockout may ameliorate kidney fibrosis by inhibition of EMT through down-regulating the AKT-mTOR and ERK1/2 pathways. This could contribute to the development of effective therapeutic strategies on chronic kidney diseases.

scholarly journals PRP4 Promotes Skin Cancer by Inhibiting Production of Melanin, Blocking Influx of Extracellular Calcium, and Remodeling Cell Actin Cytoskeleton

2021 ◽  
Vol 22 (13) ◽  
pp. 6992
Author(s):  
Muhammad Bilal Ahmed ◽  
Salman Ul Islam ◽  
Young Sup Lee
Keyword(s):  
Drug Resistance ◽  
Actin Cytoskeleton ◽  
Transient Receptor Potential ◽  
Epithelial Mesenchymal Transition ◽  
Receptor Potential ◽  
Extracellular Calcium ◽  
Melanin Biosynthesis ◽  
Mesenchymal Transition ◽  
B16f10 Cells ◽  
Transient Receptor

Pre-mRNA processing factor 4B (PRP4) has previously been shown to induce epithelial-mesenchymal transition (EMT) and drug resistance in cancer cell lines. As melanin plays an important photoprotective role in the risk of sun-induced skin cancers, we have investigated whether PRP4 can induce drug resistance and regulate melanin biosynthesis in a murine melanoma (B16F10) cell line. Cells were incubated with a crucial melanogenesis stimulator, alpha-melanocyte-stimulating hormone, followed by transfection with PRP4. This resulted in the inhibition of the production of melanin via the downregulation of adenylyl cyclase-cyclic adenosine 3’,5’-monophosphate (AC)–(cAMP)–tyrosinase synthesis signaling pathway. Inhibition of melanin production by PRP4 leads to the promotion of carcinogenesis and induced drug resistance in B16F10 cells. Additionally, PRP4 overexpression upregulated the expression of β-arrestin 1 and desensitized the extracellular calcium-sensing receptor (CaSR), which in turn, inhibited the influx of extracellular Ca2+ ions. The decreased influx of Ca2+ was confirmed by a decreased expression level of calmodulin. We have demonstrated that transient receptor potential cation channel subfamily C member 1 was involved in the influx of CaSR-induced Ca2+ via a decreasing level of its expression. Furthermore, PRP4 overexpression downregulated the expression of AC, decreased the synthesis of cAMP, and modulated the actin cytoskeleton by inhibiting the expression of Ras homolog family member A (RhoA). Our investigation suggests that PRP4 inhibits the production of melanin in B16F10 cells, blocks the influx of Ca2+ through desensitization of CaSR, and modulates the actin cytoskeleton through downregulating the AC–cAMP pathway; taken together, these observations collectively lead to the promotion of skin carcinogenesis.

Overexpression of TrpC5 promotes tumor metastasis via the HIF-1α–Twist signaling pathway in colon cancer

2017 ◽  
Vol 131 (19) ◽  
pp. 2439-2450 ◽  
Author(s):  
Zhen Chen ◽  
Yaodan Zhu ◽  
Yongfei Dong ◽  
Peng Zhang ◽  
Xiping Han ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Tumor Metastasis ◽  
Transient Receptor Potential ◽  
Epithelial Mesenchymal Transition ◽  
Hypoxia Inducible Factor ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Mesenchymal Transition

In cancer cells, intracellular Ca2+ homeostasis is altered, and this is involved in tumor initiation, progression, and metastasis. However, little is known about the underlying mechanisms. Here, we report that transient receptor potential channel 5 (TrpC5), a receptor-activated non-selective Ca2+ channel, is correlated with tumor metastasis in colon cancer patients. Moreover, in colon cancer cells, overexpression of TrpC5 caused a robust rise in the concentration of ([Ca2+]i), decreased E-cadherin, and increased mesenchymal biomarker expression, then promoted cell migration, invasion, and proliferation. Interestingly, we found that TrpC5 mediated hypoxia-inducible factor 1α (HIF-1α) expression, activating Twist to promote the epithelial–mesenchymal transition (EMT). Notably, patients with high expression of TrpC5 displayed poorer overall and metastasis-free survival. Taken together, our findings demonstrate that TrpC5 induces the EMT through the HIF-1α–Twist signaling pathway to promote tumor metastasis in colon cancer.

scholarly journals MicroRNA-150 suppresses epithelial-mesenchymal transition, invasion, and metastasis in prostate cancer through the TRPM4-mediated β-catenin signaling pathway

2019 ◽  
Vol 316 (4) ◽  
pp. C463-C480 ◽  
Author(s):  
Xi Hong ◽  
Jian-Jun Yu
Keyword(s):  
Prostate Cancer ◽  
Tumor Growth ◽  
Signaling Pathway ◽  
Transient Receptor Potential ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
Transient Receptor Potential Melastatin ◽  
Tumor Growth And Metastasis

Prostate cancer (PCa) remains one of the leading causes of cancer-related deaths among males. The aim of the current study was to investigate the ability of microRNA-150 (miR-150) targeting transient receptor potential melastatin 4 (TRPM4) to mediate epithelial-mesenchymal transition (EMT), invasion, and metastasis through the β-catenin signaling pathway in PCa. Microarray analysis was performed to identify PCa-related differentially expressed genes, after which both the mirDIP and TargetScan databases were employed in the prediction of the miRNAs regulating TRPM4. Immunohistochemistry and RT-qPCR were conducted to determine the expression pattern of miR-150 and TRPM4 in PCa. The relationship between miR-150 and TRPM4 expression was identified. By perturbing miR-150 and TRPM4 expression in PCa cells, cell proliferation, migration, invasion, cycle, and apoptosis as well as EMT markers were determined accordingly. Finally, tumor growth and metastasis were evaluated among nude mice. Higher TRPM4 expression and lower miR-150 expression and activation of the β-catenin signaling pathway as well as EMT stimulation were detected in the PCa tissues. Our results confirmed TRPM4 as a target of miR-150. Upregulation of miR-150 resulted in inactivation of the β-catenin signaling pathway. Furthermore, the upregulation of miR-150 or knockdown of TRPM4 was observed to suppress EMT, proliferation, migration, and invasion in vitro in addition to restrained tumor growth and metastasis in vivo. The evidence provided by our study highlights the involvement of miR-150 in the translational suppression of TRPM4 and the blockade of the β-catenin signaling pathway, resulting in the inhibition of PCa progression.

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.

Pharmacological Inhibition of Transient Receptor Potential Melastatin 2 (TRPM2) Channels Attenuates Diabetes-induced Cognitive Deficits in Rats: A Mechanistic Study

2020 ◽  
Vol 17 (3) ◽  
pp. 249-258 ◽  
Author(s):  
Pavan Thapak ◽  
Mahendra Bishnoi ◽  
Shyam S. Sharma
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Deficits ◽  
Ache Activity ◽  
Transient Receptor Potential ◽  
Mrna Level ◽  
Receptor Potential ◽  
Transient Receptor Potential Melastatin ◽  
Trpm2 Channels ◽  
Transient Receptor ◽  
Gsk 3Β

Background: Diabetes is a chronic metabolic disorder affecting the central nervous system. A growing body of evidence has depicted that high glucose level leads to the activation of the transient receptor potential melastatin 2 (TRPM2) channels. However, there are no studies targeting TRPM2 channels in diabetes-induced cognitive decline using a pharmacological approach. Objective: The present study intended to investigate the effects of 2-aminoethoxydiphenyl borate (2-APB), a TRPM2 inhibitor, in diabetes-induced cognitive impairment. Methods: Streptozotocin (STZ, 50 mg/kg, i.p.) was used to induce diabetes in rats. Animals were randomly divided into the treatment group, model group and age-matched control and pre se group. 2-APB treatment was given for three weeks to the animals. After 10 days of behavioural treatment, parameters were performed. Animals were sacrificed at 10th week of diabetic induction and the hippocampus and cortex were isolated. After that, protein and mRNA expression study was performed in the hippocampus. Acetylcholinesterase (AchE) activity was done in the cortex. Results: : Our study showed the 10th week diabetic animals developed cognitive impairment, which was evident from the behavioural parameters. Diabetic animals depicted an increase in the TRPM2 mRNA and protein expression in the hippocampus as well as increased AchE activity in the cortex. However, memory associated proteins were down-regulated, namely Ca2+/calmodulin-dependent protein kinase II (CaMKII-Thr286), glycogen synthase kinase 3 beta (GSK-3β-Ser9), cAMP response element-binding protein (CREB-Ser133), and postsynaptic density protein 95 (PSD-95). Gene expression of parvalbumin, calsequestrin and brain-derived neurotrophic factor (BDNF) were down-regulated while mRNA level of calcineurin A/ protein phosphatase 3 catalytic subunit alpha (PPP3CA) was upregulated in the hippocampus of diabetic animals. A three-week treatment with 2-APB significantly ameliorated the alteration in behavioural cognitive parameters in diabetic rats. Moreover, 2-APB also down-regulated the expression of TRPM2 mRNA and protein in the hippocampus as well as AchE activity in the cortex of diabetic animals as compared to diabetic animals. Moreover, the 2-APB treatment also upregulated the CaMKII (Thr-286), GSK-3β (Ser9), CREB (Ser133), and PSD-95 expression and mRNA levels of parvalbumin, calsequestrin, and BDNF while mRNA level of calcineurin A was down-regulated in the hippocampus of diabetic animals. Conclusion: : This study confirms the ameliorative effect of TRPM2 channel inhibitor in the diabetes- induced cognitive deficits. Inhibition of TRPM2 channels reduced the calcium associated downstream signaling and showed a neuroprotective effect of TRPM2 channels in diabetesinduced cognitive impairment.

Sign in / Sign up

Export Citation Format

Share Document