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1
Marshall-Gradisnik, Sonya M., Peter Smith, Ekua W. Brenu, Bernd Nilius, Sandra B. Ramos, and Donald R. Staines. "Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients." Immunology and Immunogenetics Insights 7 (January 2015): III.S25147. http://dx.doi.org/10.4137/iii.s25147.
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Background The transient receptor potential (TRP) superfamily in humans comprises 27 cation channels with permeability to monovalent and divalent cations. These channels are widely expressed within humans on cells and tissues and have significant sensory and regulatory roles on most physiological functions. Chronic fatigue syndrome (CFS) is an unexplained disorder with multiple physiological impairments. OBJECTIVES The purpose of this study was to determine the role of TRPs in CFS. Methods The study comprised 115 CFS patients (age = 48.68 ± 1.06 years) and 90 nonfatigued controls (age = 46.48 ± 1.22 years). CFS patients were defined according to the 1994 Center for Disease Prevention and Control criteria for CFS. A total of 240 single nucleotide polymorphisms (SNPs) for 21 mammalian TRP ion channel genes ( TRPA1, TRPC1, TRPC2, TRPC3, TRPC4, TRPC6, TRPC7, TRPM1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM6, TRPM7, TRPM8, TRPV1, TRPV2, TRPV3, TRPV4, TRPV5, and TRPV6) were examined via the Agena Biosciences iPLEX Gold assay. Statistical analysis was performed using the PLINK analysis software. Results Thirteen SNPs were significantly associated with CFS patients compared with the controls. Nine of these SNPs were associated with TRPM3 (rs12682832; P < 0.003, rs11142508; P < 0.004, rs1160742; P < 0.08, rs4454352; P < 0.013, rs1328153; P < 0.013, rs3763619; P < 0.014, rs7865858; P ≤ 0.021, rs1504401; P ≤ 0041, rs10115622; P ≤ 0.050), while the remainder were associated with TRPA1 (rs2383844; P ≤ 0.040, rs4738202; P ≤ 0.018) and TRPC4 (rs6650469; P ≤ 0.016, rs655207; P ≤ 0.018). Conclusion The data from this pilot study suggest an association between TRP ion channels, predominantly TRPM3 and CFS. This and other TRPs identified may contribute to the etiology and pathomechanism of CFS.
2
Yang, Xiao-Ru, Mo-Jun Lin, Lionel S. McIntosh, and James S. K. Sham. "Functional expression of transient receptor potential melastatin- and vanilloid-related channels in pulmonary arterial and aortic smooth muscle." American Journal of Physiology-Lung Cellular and Molecular Physiology 290, no. 6 (June 2006): L1267—L1276. http://dx.doi.org/10.1152/ajplung.00515.2005.
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Transient receptor potential melastatin- (TRPM) and vanilloid-related (TRPV) channels are nonselective cation channels pertinent to diverse physiological functions. Multiple TRPM and TRPV channel subtypes have been identified and cloned in different tissues. However, their information in vascular tissue is scant. In this study, we sought to identify TRPM and TRPV channel subtypes expressed in rat deendothelialized intralobar pulmonary arteries (PAs) and aorta. With RT-PCR, mRNA of TRPM2, TRPM3, TRPM4, TRPM7, and TRPM8 of TRPM family and TRPV1, TRPV2, TRPV3, and TRPV4 of TRPV family were detected in both PAs and aorta. Quantitative real-time RT-PCR showed that TRPM8 and TRPV4 were the most abundantly expressed TRPM and TRPV subtypes, respectively. Moreover, Western blot analysis verified expression of TRPM2, TRPM8, TRPV1, and TRPV4 proteins in both types of vascular tissue. To examine the functional activities of these channels, we monitored intracellular Ca2+ transients ([Ca2+]i) in pulmonary arterial smooth muscle cells (PASMCs) and aortic smooth muscle cells (ASMCs). The TRPM8 agonist menthol (300 μM) and the TRPV4 agonist 4α-phorbol 12,13-didecanoate (1 μM) evoked significant increases in [Ca2+]i in PASMCs and ASMCs. These Ca2+ responses were abolished in the absence of extracellular Ca2+ or the presence of 300 μM Ni2+ but were unaffected by 1 μM nifedipine, suggesting Ca2+ influx via nonselective cation channels. Hence, for the first time, our results indicate that multiple functional TRPM and TRPV channels are coexpressed in rat intralobar PAs and aorta. These novel Ca2+ entry pathways may play important roles in the regulation of pulmonary and systemic circulation.
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Du Preez, Stanley, Natalie Eaton-Fitch, Helene Cabanas, Donald Staines, and Sonya Marshall-Gradisnik. "Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients." International Journal of Environmental Research and Public Health 18, no. 22 (November 12, 2021): 11879. http://dx.doi.org/10.3390/ijerph182211879.
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystemic disorder responsible for significant disability. Although a unifying etiology for ME/CFS is uncertain, impaired natural killer (NK) cell cytotoxicity represents a consistent and measurable feature of this disorder. Research utilizing patient-derived NK cells has implicated dysregulated calcium (Ca2+) signaling, dysfunction of the phosphatidylinositol-4,5-bisphosphate (PIP2)-dependent cation channel, transient receptor potential melastatin (TRPM) 3, as well as altered surface expression patterns of TRPM3 and TRPM2 in the pathophysiology of ME/CFS. TRPM7 is a related channel that is modulated by PIP2 and participates in Ca2+ signaling. Though TRPM7 is expressed on NK cells, the role of TRPM7 with IL-2 and intracellular signaling mechanisms in the NK cells of ME/CFS patients is unknown. This study examined the effect of IL-2 stimulation and TRPM7 pharmacomodulation on NK cell cytotoxicity using flow cytometric assays as well as co-localization of TRPM7 with PIP2 and cortical actin using confocal microscopy in 17 ME/CFS patients and 17 age- and sex-matched healthy controls. The outcomes of this investigation are preliminary and indicate that crosstalk between IL-2 and TRMP7 exists. A larger sample size to confirm these findings and characterization of TRPM7 in ME/CFS using other experimental modalities are warranted.
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Nilius, B., F. Mahieu, Y. Karashima, and T. Voets. "Regulation of TRP channels: a voltage–lipid connection." Biochemical Society Transactions 35, no. 1 (January 22, 2007): 105–8. http://dx.doi.org/10.1042/bst0350105.
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TRP (transient receptor potential) channels respond to a plethora of stimuli in a fine-tuned manner. We show here that both membrane potential and the level of PI (phosphatidylinositol) phosphates are efficient regulators of TRP channel gating. Recent work has shown that this regulation applies to several members of the TRPV (TRP vanilloid) subfamily (TRPV1 and TRPV5) and the TRPM (TRP melastatin) subfamily (TRPM4/TRPM5/TRPM7/TRPM8), whereas regulation of members of the TRPC subfamily is still disputed. The mechanism whereby PIP2 (PI 4,5-bisphosphate) acts on TRPM4, a Ca2+- and voltage-activated channel, is shown in detail in this paper: (i) PIP2 may bind directly to the channel, (ii) PIP2 induces sensitization to activation by Ca2+, and (iii) PIP2 shifts the voltage dependence towards negative and physiologically more meaningful potentials. A PIP2-binding pocket seems to comprise a part of the TRP domain and especially pleckstrin homology domains in the C-terminus.
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Lötsch, Jörn, Dario Kringel, Gerd Geisslinger, Bruno G. Oertel, Eduard Resch, and Sebastian Malkusch. "Machine-Learned Association of Next-Generation Sequencing-Derived Variants in Thermosensitive Ion Channels Genes with Human Thermal Pain Sensitivity Phenotypes." International Journal of Molecular Sciences 21, no. 12 (June 19, 2020): 4367. http://dx.doi.org/10.3390/ijms21124367.
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Genetic association studies have shown their usefulness in assessing the role of ion channels in human thermal pain perception. We used machine learning to construct a complex phenotype from pain thresholds to thermal stimuli and associate it with the genetic information derived from the next-generation sequencing (NGS) of 15 ion channel genes which are involved in thermal perception, including ASIC1, ASIC2, ASIC3, ASIC4, TRPA1, TRPC1, TRPM2, TRPM3, TRPM4, TRPM5, TRPM8, TRPV1, TRPV2, TRPV3, and TRPV4. Phenotypic information was complete in 82 subjects and NGS genotypes were available in 67 subjects. A network of artificial neurons, implemented as emergent self-organizing maps, discovered two clusters characterized by high or low pain thresholds for heat and cold pain. A total of 1071 variants were discovered in the 15 ion channel genes. After feature selection, 80 genetic variants were retained for an association analysis based on machine learning. The measured performance of machine learning-mediated phenotype assignment based on this genetic information resulted in an area under the receiver operating characteristic curve of 77.2%, justifying a phenotype classification based on the genetic information. A further item categorization finally resulted in 38 genetic variants that contributed most to the phenotype assignment. Most of them (10) belonged to the TRPV3 gene, followed by TRPM3 (6). Therefore, the analysis successfully identified the particular importance of TRPV3 and TRPM3 for an average pain phenotype defined by the sensitivity to moderate thermal stimuli.
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Müller, Isabel, Philipp Alt, Suhasini Rajan, Lena Schaller, Fabienne Geiger, and Alexander Dietrich. "Transient Receptor Potential (TRP) Channels in Airway Toxicity and Disease: An Update." Cells 11, no. 18 (September 17, 2022): 2907. http://dx.doi.org/10.3390/cells11182907.
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Our respiratory system is exposed to toxicants and pathogens from both sides: the airways and the vasculature. While tracheal, bronchial and alveolar epithelial cells form a natural barrier in the airways, endothelial cells protect the lung from perfused toxic compounds, particulate matter and invading microorganism in the vascular system. Damages induce inflammation by our immune response and wound healing by (myo)fibroblast proliferation. Members of the transient receptor potential (TRP) superfamily of ion channel are expressed in many cells of the respiratory tract and serve multiple functions in physiology and pathophysiology. TRP expression patterns in non-neuronal cells with a focus on TRPA1, TRPC6, TRPM2, TRPM5, TRPM7, TRPV2, TRPV4 and TRPV6 channels are presented, and their roles in barrier function, immune regulation and phagocytosis are summarized. Moreover, TRP channels as future pharmacological targets in chronic obstructive pulmonary disease (COPD), asthma, cystic and pulmonary fibrosis as well as lung edema are discussed.
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Islam, Md Shahidul. "Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells." Cells 9, no. 3 (March 11, 2020): 685. http://dx.doi.org/10.3390/cells9030685.
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Insulin secretion from the β-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, and numerous ion channels that mediate the electrical activity. Several members of the transient receptor potential (TRP) channels participate in the processes that mediate the electrical activities and Ca2+ oscillations in these cells. Human β-cells express TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3 channels. Some of these channels have been reported to mediate background depolarizing currents, store-operated Ca2+ entry (SOCE), electrical activity, Ca2+ oscillations, gene transcription, cell-death, and insulin secretion in response to stimulation by glucose and GLP1. Different channels of the TRP family are regulated by one or more of the following mechanisms: activation of G protein-coupled receptors, the filling state of the endoplasmic reticulum Ca2+ store, heat, oxidative stress, or some second messengers. This review briefly compiles our current knowledge about the molecular mechanisms of regulations, and functions of the TRP channels in the β-cells, the α-cells, and some insulinoma cell lines.
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Andriulė, Inga, Dalia Pangonytė, Asfree Gwanyanya, Dainius Karčiauskas, Kanigula Mubagwa, and Regina Mačianskienė. "Detection of TRPM6 and TRPM7 Proteins in Normal and Diseased Cardiac Atrial Tissue and Isolated Cardiomyocytes." International Journal of Molecular Sciences 23, no. 23 (November 28, 2022): 14860. http://dx.doi.org/10.3390/ijms232314860.
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Magnesium-sensitive transient receptor potential melastatin (TRPM) ion channels, TRPM6 and TRPM7, are present in several organs, but their roles in the heart remain unclear. Therefore, here, we studied the expression patterns of TRPM6 and TRPM7 in normal and diseased myocardium. Cardiac atrial tissue and cardiomyocytes were obtained from healthy pigs and undiseased human hearts as well as from hearts of patients with ischemic heart disease (IHD) or atrial fibrillation (AF). Immunofluorescence and ELISA were used to detect TRP proteins. TRPM6 and TRPM7 immunofluorescence signals, localized at/near the cell surface or intracellularly, were detected in pig and human atrial tissues. The TRP channel modulators carvacrol (CAR, 100 µM) or 2-aminoethoxydiphenyl borate (2-APB, 500 µM) decreased the TRPM7 signal, but enhanced that of TRPM6. At a higher concentration (2 mM), 2-APB enhanced the signals of both proteins. TRPM6 and TRPM7 immunofluorescence signals and protein concentrations were increased in atrial cells and tissues from IHD or AF patients. TRPM6 and TRPM7 proteins were both detected in cardiac atrial tissue, with relatively similar subcellular localization, but distinctive drug sensitivity profiles. Their upregulated expression in IHD and AF suggests a possible role of the channels in cardiac atrial disease.
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Özcan, SS, G. Gürel, and M. Çakır. "Gene expression profiles of transient receptor potential (TRP) channels in the peripheral blood mononuclear cells of psoriasis patients." Human & Experimental Toxicology 40, no. 8 (February 8, 2021): 1234–40. http://dx.doi.org/10.1177/0960327121991911.
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Psoriasis is a chronic autoimmune disease in which peripheral blood mononuclear cells (PBMCs) are involved in the pathological process. Transient receptor potential (TRP) channels expressed in immune cells have been shown to be associated with inflammatory diseases. We aimed to evaluate mRNA expression levels of TRP channels in PBMCs of patients with psoriasis. 30 patients with plaque psoriasis and 30 healthy age- and gender-matched control subjects were included in this study. mRNA expression levels of TRP channels in psoriasis patients were determined by Real-time polymerase chain reaction. A decreased TRPM4, TRPM7, TRPV3, TRPV4, and TRPC6 genes expression levels were found in the patient group compared to controls, respectively ( p = 0.045, p = 0.000, p = 0.000, p = 0.045, p = 0.009), whereas, an increased expression level was found in TRPM2 and TRPV1 genes in the patient group compared to controls ( p = 0.001 and p = 0.028). This is the first study showing the TRP channel mRNA expressions in PBMCs of psoriasis patients. Different expression patterns of TRP channels may have a role in pathogenesis of psoriasis.
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Scharenberg, Andrew M. "TRPM2 and TRPM7: channel/enzyme fusions to generate novel intracellular sensors." Pflügers Archiv - European Journal of Physiology 451, no. 1 (July 7, 2005): 220–27. http://dx.doi.org/10.1007/s00424-005-1444-0.
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Hermosura, Meredith C., and Ralph M. Garruto. "TRPM7 and TRPM2—Candidate susceptibility genes for Western Pacific ALS and PD?" Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1772, no. 8 (August 2007): 822–35. http://dx.doi.org/10.1016/j.bbadis.2007.02.008.
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Li, Mingjiang, Jianmin Jiang, and Lixia Yue. "Functional Characterization of Homo- and Heteromeric Channel Kinases TRPM6 and TRPM7." Journal of General Physiology 127, no. 5 (April 24, 2006): 525–37. http://dx.doi.org/10.1085/jgp.200609502.
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TRPM6 and TRPM7 are two known channel kinases that play important roles in various physiological processes, including Mg2+ homeostasis. Mutations in TRPM6 cause hereditary hypomagnesemia and secondary hypocalcemia (HSH). However, whether TRPM6 encodes functional channels is controversial. Here we demonstrate several signature features of TRPM6 that distinguish TRPM6 from TRPM7 and TRPM6/7 channels. We show that heterologous expression of TRPM6 but not the mutant TRPM6S141L produces functional channels with divalent cation permeability profile and pH sensitivity distinctive from those of TRPM7 channels and TRPM6/7 complexes. TRPM6 exhibits unique unitary conductance that is 2- and 1.5-fold bigger than that of TRPM7 and TRPM6/7. Moreover, micromolar levels of 2-aminoethoxydiphenyl borate (2-APB) maximally increase TRPM6 but significantly inhibit TRPM7 channel activities; whereas millimolar concentrations of 2-APB potentiate TRPM6/7 and TRPM7 channel activities. Furthermore, Mg2+ and Ca2+ entry through TRPM6 is enhanced three- to fourfold by 2-APB. Collectively, these results indicate that TRPM6 forms functional homomeric channels as well as heteromeric TRPM6/7 complexes. The unique characteristics of these three channel types, TRPM6, TRPM7, and TRPM6/7, suggest that they may play different roles in vivo.
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Touyz, Rhian M. "Transient receptor potential melastatin 6 and 7 channels, magnesium transport, and vascular biology: implications in hypertension." American Journal of Physiology-Heart and Circulatory Physiology 294, no. 3 (March 2008): H1103—H1118. http://dx.doi.org/10.1152/ajpheart.00903.2007.
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Magnesium, an essential intracellular cation, is critically involved in many biochemical reactions involved in the regulation of vascular tone and integrity. Decreased magnesium concentration has been implicated in altered vascular reactivity, endothelial dysfunction, vascular inflammation, and structural remodeling, processes important in vascular changes and target organ damage associated with hypertension. Until recently, very little was known about mechanisms regulating cellular magnesium homeostasis, and processes controlling transmembrane magnesium transport had been demonstrated only at the functional level. Two cation channels of the transient receptor potential melastatin (TRPM) cation channel family have now been identified as magnesium transporters, TRPM6 and TRPM7. These unique proteins, termed chanzymes because they possess a channel and a kinase domain, are differentially expressed, with TRPM6 being found primarily in epithelial cells and TRPM7 occurring ubiquitously. Vascular TRPM7 is modulated by vasoactive agents, pressure, stretch, and osmotic changes and may be a novel mechanotransducer. In addition to its magnesium transporter function, TRPM7 has been implicated as a signaling kinase involved in vascular smooth muscle cell growth, apoptosis, adhesion, contraction, cytoskeletal organization, and migration, important processes involved in vascular remodeling associated with hypertension and other vascular diseases. Emerging evidence suggests that vascular TRPM7 function may be altered in hypertension. This review discusses the importance of magnesium in vascular biology and implications in hypertension and highlights the transport systems, particularly TRPM6 and TRPM7, which may play a role in the control of vascular magnesium homeostasis. Since the recent identification and characterization of Mg2+-selective transporters, there has been enormous interest in the field. However, there is still a paucity of information, and much research is needed to clarify the exact mechanisms of magnesium regulation in the cardiovascular system and the implications of aberrant transmembrane magnesium transport in the pathogenesis of hypertension and other vascular diseases.
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Kovács, Zsigmond Máté, Csaba Dienes, Tamás Hézső, János Almássy, János Magyar, Tamás Bányász, Péter P. Nánási, Balázs Horváth, and Norbert Szentandrássy. "Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 1: Modulation of TRPM4." Pharmaceuticals 15, no. 1 (January 10, 2022): 81. http://dx.doi.org/10.3390/ph15010081.
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Transient receptor potential melastatin 4 is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+-sensitive and permeable to monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions by regulating the membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. This part of the review discusses the pharmacological modulation of TRPM4 by listing, comparing, and describing both endogenous and exogenous activators and inhibitors of the ion channel. Moreover, other strategies used to study TRPM4 functions are listed and described. These strategies include siRNA-mediated silencing of TRPM4, dominant-negative TRPM4 variants, and anti-TRPM4 antibodies. TRPM4 is receiving more and more attention and is likely to be the topic of research in the future.
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Saito, Shigeru, and Ryuzo Shingai. "Evolution of thermoTRP ion channel homologs in vertebrates." Physiological Genomics 27, no. 3 (December 2006): 219–30. http://dx.doi.org/10.1152/physiolgenomics.00322.2005.
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In mammalian thermosensation, nine temperature-sensitive ion channels that are activated by distinct temperature thresholds have been identified as thermosensors. These ion channels belong to the transient receptor potential (TRP) superfamily and are referred to as “thermoTRPs” (TRPV1, TRPV2, TRPV3, TRPV4, TRPM2, TRPM4, TRPM5, TRPM8, and TRPA1). To elucidate the evolutionary processes of thermoTRPs, we conducted comprehensive searches for mammalian thermoTRP gene homologs in the draft genome sequences of chicken ( Gallus gallus), western clawed frog ( Xenopus tropicalis), zebrafish ( Danio rerio), and pufferfish ( Fugu rubripes). Newly identified homologs were compared with known thermoTRPs, and phylogenetic analyses were conducted. Our comparative analyses revealed that most of the mammalian thermo-TRP members already existed in the common ancestor of fishes and tetrapods. Tetrapods shared almost the same repertoire, except that the western clawed frog expanded TRPV4s (six copies) and TRPM8s (two copies), which were diversified considerably. Comparisons of nonsynonymous and synonymous substitution rates among TRPV4s suggested that one copy of the TRPV4 channel in the western clawed frog retained its original function, while the other copies diversified and obtained slightly different properties. In fish lineages, several members of thermo-TRPs have duplicated in the whole genome duplication occurred in the ancestral ray-finned fish; however, some of the copies have subsequently been lost. Furthermore, fishes do not possess the three members of thermoTRPs existed in mammals, e.g., thermoTRPs activated by noxious heat, warm, and cool temperatures. Our results suggest that thermosensation mechanisms have changed through vertebrate evolution with respect to thermosensor repertoires.
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Touyz, Rhian M., Ying He, Augusto C. I. Montezano, Guoying Yao, Vladimir Chubanov, Thomas Gudermann, and Glaucia E. Callera. "Differential regulation of transient receptor potential melastatin 6 and 7 cation channels by ANG II in vascular smooth muscle cells from spontaneously hypertensive rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 290, no. 1 (January 2006): R73—R78. http://dx.doi.org/10.1152/ajpregu.00515.2005.
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Intracellular Mg2+ depletion has been implicated in vascular dysfunction in hypertension. We demonstrated that transient receptor potential melastatin 7 (TRPM7) cation channels mediate Mg2+ influx in VSMCs. Whether this plays a role in [Mg2+]i deficiency in hypertension is unclear. Here, we tested the hypothesis that downregulation of TRPM7 and its homologue TRPM6 is associated with reduced [Mg2+]i and that ANG II negatively regulates TRPM6/7 in vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats (SHR). Cultured VSMCs from Wistar Kyoto (WKY) and SHR were studied. mRNA and protein expression of TRPM6 and TRPM7 were assessed by RT-PCR and immunoblotting, respectively. Translocation of annexin-1, specific TRPM7 substrate, was measured as an index of TRPM7 activation. [Mg2+]i was determined using mag fura-2. VSMCs from WKY and SHR express TRPM6 and TRPM7. Basal TRPM6 expression was similar in WKY and SHR, but basal TRPM7 content was lower in VSMCs from SHR vs. WKY. This was associated with significantly reduced [Mg2+]i in SHR cells ( P < 0.01). ANG II time-dependently increased TRPM6 expression, with similar responses in WKY and SHR. ANG II significantly increased TRPM7 expression in WKY ( P < 0.05), but not in SHR. Annexin-1 translocation was reduced 1.5–2-fold in SHR vs. WKY. Our findings demonstrate that TRPM6 and TRPM7 are differentially regulated in VSMCs from SHR and WKY. Whereas TRPM6 is unaltered in SHR, expression of TRPM7 is blunted. This was associated with attenuated annexin-1 translocation and decreased VSMC [Mg2+]i in SHR. Downregulation of TRPM7, but not TRPM6, may play a role in altered Mg2+ homeostasis in VSMCs from SHR.
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Oberwinkler, J. "TRPM3, a biophysical enigma?" Biochemical Society Transactions 35, no. 1 (January 22, 2007): 89–90. http://dx.doi.org/10.1042/bst0350089.
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TRPM3 [TRP (transient receptor potential) melastatin 3] is one of the least investigated proteins of the TRP family of ion channels. Heterologously expressed TRPM3 channels are constitutively active, have an outwardly rectifying current–voltage relationship and are inhibited by intracellular Mg2+ ions. Besides these rather common features, in which TRPM3 channels resemble the closely related channels TRPM6 and TRPM7, TRPM3 channels have several unique characteristics. The TRPM3 gene encodes a plethora of different proteins owing to alternative splicing and alternative exon usage. One site of alternative splicing affects the ion-conducting pore region and profoundly alters the pore properties of the encoded channels. The channels having the longer pore region efficiently conduct univalent cations, but are only poorly permeated by bivalent cations. Conversely, the channels with the shorter pore region are highly permeable to bivalent cations. Unusually, the short-pore TRPM3 channels are inhibited by extracellular Na+ ions. At physiological sodium concentration, this block is very strong, making it difficult to envision a physiological function for these ion channels. Recently, pharmacological investigations have been initiated in order to identify substances that influence TRPM3 channel activity. With the use of such substances, it might be possible to identify TRPM3 channels in their native environment and to elucidate some of their physiological roles. Hopefully, TRPM3 channels will then no longer appear to be as enigmatic as they do right now.
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Dienes, Csaba, Zsigmond Máté Kovács, Tamás Hézső, János Almássy, János Magyar, Tamás Bányász, Péter P. Nánási, Balázs Horváth, and Norbert Szentandrássy. "Pharmacological Modulation and (Patho)Physiological Roles of TRPM4 Channel—Part 2: TRPM4 in Health and Disease." Pharmaceuticals 15, no. 1 (December 28, 2021): 40. http://dx.doi.org/10.3390/ph15010040.
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Transient receptor potential melastatin 4 (TRPM4) is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+ sensitive and permeable for monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions; it regulates membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. This part of the review discusses the currently available knowledge about the physiological and pathophysiological roles of TRPM4 in various tissues. These include the physiological functions of TRPM4 in the cells of the Langerhans islets of the pancreas, in various immune functions, in the regulation of vascular tone, in respiratory and other neuronal activities, in chemosensation, and in renal and cardiac physiology. TRPM4 contributes to pathological conditions such as overactive bladder, endothelial dysfunction, various types of malignant diseases and central nervous system conditions including stroke and injuries as well as in cardiac conditions such as arrhythmias, hypertrophy, and ischemia-reperfusion injuries. TRPM4 claims more and more attention and is likely to be the topic of research in the future.
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Zou, Zhi-Guo, Francisco J. Rios, Augusto C. Montezano, and Rhian M. Touyz. "TRPM7, Magnesium, and Signaling." International Journal of Molecular Sciences 20, no. 8 (April 16, 2019): 1877. http://dx.doi.org/10.3390/ijms20081877.
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The transient receptor potential melastatin-subfamily member 7 (TRPM7) is a ubiquitously expressed chanzyme that possesses an ion channel permeable to the divalent cations Mg2+, Ca2+, and Zn2+, and an α-kinase that phosphorylates downstream substrates. TRPM7 and its homologue TRPM6 have been implicated in a variety of cellular functions and is critically associated with intracellular signaling, including receptor tyrosine kinase (RTK)-mediated pathways. Emerging evidence indicates that growth factors, such as EGF and VEGF, signal through their RTKs, which regulate activity of TRPM6 and TRPM7. TRPM6 is primarily an epithelial-associated channel, while TRPM7 is more ubiquitous. In this review we focus on TRPM7 and its association with growth factors, RTKs, and downstream kinase signaling. We also highlight how interplay between TRPM7, Mg2+ and signaling kinases influences cell function in physiological and pathological conditions, such as cancer and preeclampsia.
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Krapivinsky, Grigory, Luba Krapivinsky, Nora E. Renthal, Ana Santa-Cruz, Yunona Manasian, and David E. Clapham. "Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression." Proceedings of the National Academy of Sciences 114, no. 34 (August 7, 2017): E7092—E7100. http://dx.doi.org/10.1073/pnas.1708427114.
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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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Yamaguchi, Soichiro, Akira Tanimoto, Shinsuke Iwasa, and Ken-ichi Otsuguro. "TRPM4 and TRPM5 Channels Share Crucial Amino Acid Residues for Ca2+ Sensitivity but Not Significance of PI(4,5)P2." International Journal of Molecular Sciences 20, no. 8 (April 24, 2019): 2012. http://dx.doi.org/10.3390/ijms20082012.
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Transient receptor potential melastatin member 4 (TRPM4) and 5 (TRPM5) channels are Ca2+-activated nonselective cation channels. Intracellular Ca2+ is the most important regulator for them to open, though PI(4,5)P2, a membrane phosphoinositide, has been reported to regulate their Ca2+-sensitivities. We previously reported that negatively-charged amino acid residues near and in the TRP domain are necessary for the normal Ca2+ sensitivity of TRPM4. More recently, a cryo-electron microscopy structure of Ca2+-bound (but closed) TRPM4 was reported, proposing a Ca2+-binding site within an intracellular cavity formed by S2 and S3. Here, we examined the functional effects of mutations of the amino acid residues related to the proposed Ca2+-binding site on TRPM4 and also TRPM5 using mutagenesis and patch clamp techniques. The mutations of the amino acid residues of TRPM4 and TRPM5 reduced their Ca2+-sensitivities in a similar way. On the other hand, intracellular applications of PI(4,5)P2 recovered Ca2+-sensitivity of desensitized TRPM4, but its effect on TRPM5 was negligible. From these results, the Ca2+-binding sites of TRPM4 and TRPM5 were shown to be formed by the same amino acid residues by functional analyses, but the impact of PI(4,5)P2 on the regulation of TRPM5 seemed to be smaller than that on the regulation of TRPM4.
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Gouadon, Elodie, Florence Lecerf, and Michèle German-Fattal. "Differential Effects of Cyclosporin A and Tacrolimus on Magnesium Influx in Caco2 Cells." Journal of Pharmacy & Pharmaceutical Sciences 15, no. 3 (June 18, 2012): 389. http://dx.doi.org/10.18433/j3qk57.
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PURPOSE: Hypomagnesemia with urinary magnesium (Mg) wasting is a well acknowledged side effect of cyclosporin A (CsA) and tacrolimus (FK506) treatments. TRPM6, TRPM7 and MagT1 are involved in the active transcellular Mg transport processes in intestine and kidney. Since Mg homeostasis is tightly controlled by the dynamic action of intestinal absorption of dietary Mg and renal excretion of Mg, we investigated whether CsA and FK506 in commercially available solutions for clinical use decrease the expression and the function of TRPM6, TRPM7 or MagT1 in the intestinal epithelial cell line Caco2. METHODS: Changes of intracellular free Mg concentrations were measured by Mag-fura-2 imaging in Mg-free medium after the addition of 1 mM MgCl2. TRPM6, TRPM7 and MagT1 were evidenced in cells by immunofluorescence. Proteins and mRNAs were quantified after 18 hours of treatment with CsA or FK506 by western-blot and real-time RT-PCR analyses, respectively. RESULTS: TRPM6 and MagT1 were evidenced on all cell membranes, TRPM7 only on the inner membranes. CsA was responsible for a profound decrease in Mg2+ influx in intestinal epithelial cells, which may result in a decrease of intestinal Mg absorption, whereas FK506 was responsible for a marked increase in Mg2+ influx. Neither CsA nor FK506 altered TRPM6, TRPM7 or MagT1 mRNA levels or MagT1 protein level. CONCLUSIONS: In Caco2 cells, Mg2+ influx was inhibited by CsA solutions whereas enhanced by FK506 solutions, without alteration of MagT1, TRPM6 and TRPM7 expression, leading to the conclusion that CsA and FK506 have opposite effects in the functional activity of the Mg transporters herein examined. In clinical use, FK506 should be preferred for patients at risk for hypomagnesemia.
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Robak, Paulina, Małgorzata Ożgo, Katarzyna Michałek, Agnieszka Kolasa-Wołosiuk, Marcin Taciak, Marcin Barszcz, and Marta Marynowska. "Identification of TRPM6 and TRPM7 expression changes in response to a diet supplemented with inulin in porcine kidney." Archives Animal Breeding 59, no. 2 (June 14, 2016): 267–74. http://dx.doi.org/10.5194/aab-59-267-2016.
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Abstract. Magnesium is the fourth most abundant mineral element in vertebrates and the second most common intracellular cation. Recently identified Mg2+-specific channels – TRPM6 and TRPM7 – have been shown to be essential for whole-body and cellular Mg2+ homeostasis. The aim of the study was to determine the effect of inulin on the expression of TRPM6 and TRPM7 in the renal cortex and medulla of growing pigs. The study was carried out on 16 Danbred × Duroc castrated male piglets fed a cereal-based diet without inulin or with 2 % addition of inulin from chicory root from the 10th day of life. In pigs fed a diet with inulin, TRPM6 expression was greater in both the renal cortex and medulla compared to the control group. The expression of TRPM7 in both the renal cortex and medulla in the control group and in piglets fed a diet enriched with inulin was relatively stable. To our knowledge, this is the first study aimed at the identification of TRPM6 and TRPM7 in the kidneys of pig. It is proposed that inulin addition to fodder resulted not only in a magnesium absorption increase, but also, due to prolonged low plasma Mg concentration of examined piglets, renal magnesium retention. Therefore, higher magnesium reabsorption via increased TRPM6 expression in the kidney was probably observed in order to supplement deficiencies of this element. Diet-unresponsive expression of TRPM7 supports the concept that this channel is not involved in the extracellular magnesium homeostasis.
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Shi, Ruixue, Yu Fu, Dongyi Zhao, Tomasz Boczek, Wuyang Wang, and Feng Guo. "Cell death modulation by transient receptor potential melastatin channels TRPM2 and TRPM7 and their underlying molecular mechanisms." Biochemical Pharmacology 190 (August 2021): 114664. http://dx.doi.org/10.1016/j.bcp.2021.114664.
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Everaerts, Wouter, Joris Vriens, Grzegorz Owsianik, Giovanni Appendino, Thomas Voets, Dirk De Ridder, and Bernd Nilius. "Functional characterization of transient receptor potential channels in mouse urothelial cells." American Journal of Physiology-Renal Physiology 298, no. 3 (March 2010): F692—F701. http://dx.doi.org/10.1152/ajprenal.00599.2009.
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The bladder urothelium is currently believed to be a sensory structure, contributing to mechano- and chemosensation in the bladder. Transient receptor potential (TRP) cation channels act as polymodal sensors and may underlie some of the receptive properties of urothelial cells. However, the exact TRP channel expression profile of urothelial cells is unclear. In this study, we have performed a systematic analysis of the molecular and functional expression of various TRP channels in mouse urothelium. Urothelial cells from control and trpv4−/− mice were isolated, cultured (12–48 h), and used for quantitative real-time PCR, immunocytochemistry, calcium imaging, and whole cell patch-clamp experiments. At the mRNA level, TRPV4, TRPV2, and TRPM7 were the most abundantly expressed TRP genes. Immunohistochemistry showed a clear expression of TRPV4 in the plasma membrane, whereas TRPV2 was more prominent in the cytoplasm. TRPM7 was detected in the plasma membrane as well as cytoplasmic vesicles. Calcium imaging and patch-clamp experiments using TRP channel agonists and antagonists provided evidence for the functional expression of TRPV4, TRPV2, and TRPM7 but not of TRPA1, TRPV1, and TRPM8. In conclusion, we have demonstrated functional expression of TRPV4, TRPV2, and TRPM7 in mouse urothelial cells. These channels may contribute to the (mechano)sensory function of the urothelial layer and represent potential targets for the treatment of bladder dysfunction.
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Kühn, Frank J. P., Gabriel Knop, and Andreas Lückhoff. "The Transmembrane Segment S6 Determines Cation versus Anion Selectivity of TRPM2 and TRPM8." Journal of Biological Chemistry 282, no. 38 (June 29, 2007): 27598–609. http://dx.doi.org/10.1074/jbc.m702247200.
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TRPM2 and TRPM8, closely related members of the transient receptor potential (TRP) family, are cation channels activated by quite different mechanisms. Their transmembrane segments S5 and S6 are highly conserved. To identify common structures in S5 and S6 that govern interaction with the pore, we created a chimera in which the S5-pore-S6 region of TRPM8 was inserted into TRPM2, along with a lysine at each transition site. Currents through this chimera were induced by ADP-ribose (ADPR) in cooperation with Ca2+. In contrast to wild-type TRPM2 channels, currents through the chimera were carried by Cl-, as demonstrated in ion substitution experiments using the cation N-methyl-d-glucamine (NMDG) and the anion glutamate. Extracellular NMDG had no effects. The substitution of either intracellular or extracellular Cl- with glutamate shifted the reversal potential, decreased the current amplitude and induced a voltage-dependent block relieved by depolarization. The lysine in S6 was responsible for the anion selectivity; insertion of a lysine into corresponding sites within S6 of either TRPM2 or TRPM8 created anion channels that were activated by ADPR (TRPM2 I1045K) or by cold temperatures (TRPM8 V976K). The positive charge of the lysine was decisive for the glutamate block because the mutant TRPM2 I1045H displayed cation currents that were blocked at acidic but not alkaline intracellular pH values. We conclude that the distal part of S6 is crucial for the discrimination of charge. Because of the high homology of S6 in the whole TRP family, this new role of S6 may apply to further TRP channels.
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Etem, Ebru Onalan, Ramazan Bal, Arzu Etem Akağaç, Tuncay Kuloglu, Mehmet Tuzcu, Grigory V. Andrievsky, Ilay Buran, Victor S. Nedzvetsky, and Gıyasettin Baydas. "The effects of hydrated C(60) fullerene on gene expression profile of TRPM2 and TRPM7 in hyperhomocysteinemic mice." Journal of Receptors and Signal Transduction 34, no. 4 (March 19, 2014): 317–24. http://dx.doi.org/10.3109/10799893.2014.896381.
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Inoue, Koichi, Zhi-Gang Xiong, and Takatoshi Ueki. "The TRPM7 Channel in the Nervous and Cardiovascular Systems." Current Protein & Peptide Science 21, no. 10 (December 31, 2020): 985–92. http://dx.doi.org/10.2174/1389203721666200605170938.
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: 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.
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Dutta Banik, Debarghya, Laura E. Martin, Marc Freichel, Ann-Marie Torregrossa, and Kathryn F. Medler. "TRPM4 and TRPM5 are both required for normal signaling in taste receptor cells." Proceedings of the National Academy of Sciences 115, no. 4 (January 8, 2018): E772—E781. http://dx.doi.org/10.1073/pnas.1718802115.
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Peripheral taste receptor cells use multiple signaling pathways to transduce taste stimuli into output signals that are sent to the brain. Transient receptor potential melastatin 5 (TRPM5), a sodium-selective TRP channel, functions as a common downstream component in sweet, bitter, and umami signaling pathways. In the absence of TRPM5, mice have a reduced, but not abolished, ability to detect stimuli, suggesting that a TRPM5-independent pathway also contributes to these signals. Here, we identify a critical role for the sodium-selective TRP channel TRPM4 in taste transduction. Using live cell imaging and behavioral studies in KO mice, we show that TRPM4 and TRPM5 are both involved in taste-evoked signaling. Loss of either channel significantly impairs taste, and loss of both channels completely abolishes the ability to detect bitter, sweet, or umami stimuli. Thus, both TRPM4 and TRPM5 are required for transduction of taste stimuli.
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Oronowicz, Jakub, Jacqueline Reinhard, Peter Sol Reinach, Szymon Ludwiczak, Huan Luo, Marah Hussain Omar Ba Salem, Miriam Monika Kraemer, Heike Biebermann, Vinodh Kakkassery, and Stefan Mergler. "Ascorbate-induced oxidative stress mediates TRP channel activation and cytotoxicity in human etoposide-sensitive and -resistant retinoblastoma cells." Laboratory Investigation 101, no. 1 (September 18, 2020): 70–88. http://dx.doi.org/10.1038/s41374-020-00485-2.
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AbstractThere are indications that pharmacological doses of ascorbate (Asc) used as an adjuvant improve the chemotherapeutic management of cancer. This favorable outcome stems from its cytotoxic effects due to prooxidative mechanisms. Since regulation of intracellular Ca2+ levels contributes to the maintenance of cell viability, we hypothesized that one of the effects of Asc includes disrupting regulation of intracellular Ca2+ homeostasis. Accordingly, we determined if Asc induced intracellular Ca2+ influx through activation of pertussis sensitive Gi/o-coupled GPCR which in turn activated transient receptor potential (TRP) channels in both etoposide-resistant and -sensitive retinoblastoma (WERI-Rb1) tumor cells. Ca2+ imaging, whole-cell patch-clamping, and quantitative real-time PCR (qRT-PCR) were performed in parallel with measurements of RB cell survival using Trypan Blue cell dye exclusion. TRPM7 gene expression levels were similar in both cell lines whereas TRPV1, TRPM2, TRPA1, TRPC5, TRPV4, and TRPM8 gene expression levels were downregulated in the etoposide-resistant WERI-Rb1 cells. In the presence of extracellular Ca2+, 1 mM Asc induced larger intracellular Ca2+ transients in the etoposide-resistant WERI-Rb1 than in their etoposide-sensitive counterpart. With either 100 µM CPZ, 500 µM La3+, 10 mM NAC, or 100 µM 2-APB, these Ca2+ transients were markedly diminished. These inhibitors also had corresponding inhibitory effects on Asc-induced rises in whole-cell currents. Pertussis toxin (PTX) preincubation blocked rises in Ca2+ influx. Microscopic analyses showed that after 4 days of exposure to 1 mM Asc cell viability fell by nearly 100% in both RB cell lines. Taken together, one of the effects underlying oxidative mediated Asc-induced WERI-Rb1 cytotoxicity stems from its promotion of Gi/o coupled GPCR mediated increases in intracellular Ca2+ influx through TRP channels. Therefore, designing drugs targeting TRP channel modulation may be a viable approach to increase the efficacy of chemotherapeutic treatment of RB. Furthermore, Asc may be indicated as a possible supportive agent in anti-cancer therapies.
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Dragún, Martin, Andrea Gažová, Ján Kyselovič, Michal Hulman, and Marek Máťuš. "TRP Channels Expression Profile in Human End-Stage Heart Failure." Medicina 55, no. 7 (July 16, 2019): 380. http://dx.doi.org/10.3390/medicina55070380.
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Objectives: Many studies indicate the involvement of transient receptor potential (TRP) channels in the development of heart hypertrophy. However, the data is often conflicted and has originated in animal models. Here, we provide systematic analysis of TRP channels expression in human failing myocardium. Methods and results: Left-ventricular tissue samples were isolated from explanted hearts of NYHA III-IV patients undergoing heart transplants (n = 43). Quantitative real-time PCR was performed to assess the mRNA levels of TRPC, TRPM and TRPV channels. Analysis of functional, clinical and biochemical data was used to confirm an end-stage heart failure diagnosis. Compared to myocardium samples from healthy donor hearts (n = 5), we detected a distinct increase in the expression of TRPC1, TRPC5, TRPM4 and TRPM7, and decreased expression of TRPC4 and TRPV2. These changes were not dependent on gender, clinical or biochemical parameters, nor functional parameters of the heart. We detected, however, a significant correlation of TRPC1 and MEF2c expression. Conclusions: The end-stage heart failure displays distinct expressional changes of TRP channels. Our findings provide a systematic description of TRP channel expression in human heart failure. The results highlight the complex interplay between TRP channels and the need for deeper analysis of early stages of hypertrophy and heart failure development.
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Chung, Gehoon, and Seog Bae Oh. "TRP Channels in Dental Pain." Open Pain Journal 6, no. 1 (March 8, 2013): 31–36. http://dx.doi.org/10.2174/1876386301306010031.
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Despite the high incidence of dental pain, the mechanism underlying its generation is mostly unknown. Functional expression of temperature-sensitive transient receptor potential (thermo-TRP) channels, such as TRPV1, TRPV2, TRPM8, and TRPA1 in dental primary afferent neurons and TRPV1, TRPV2, TRPV3, TRPV4, and TRPM3 in odontoblasts, has been demonstrated and suggested as responsible for dental pain elicited by hot and cold food. However, dental pain induced by light touch or sweet substance cannot be explained by the role of thermo-TRP channels. Most of current therapeutics of dentin hypersensitivity is based on hydrodynamic theory, which argues that light stimuli such as air puff and temperature changes cause fluid movement within dentinal tubule, which is then transduced as pain. To test this theory, various TRP channels as candidates of cellular mechanotransducers were studied for expression in dental primary afferents and odontoblasts. The expression of TRPV1, TRPV2, TRPA1, TRPV4, and TRPM3 in trigeminal neurons and TRPV1, TRPV2, TRPV3, TRPV4 and TRPM3 in odontoblasts has been revealed. However, their roles as cellular mechanotransducers are controversial and contribution to generation of dental pain is still elusive. This review discusses recent advances in understanding of molecular mechanism underlying development of dental pain.
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Ibrahim, Dakik, Vandier, Chautard, Paintaud, Mazurier, Lecomte, Guéguinou, and Raoul. "Expression Profiling of Calcium Channels and Calcium-Activated Potassium Channels in Colorectal Cancer." Cancers 11, no. 4 (April 19, 2019): 561. http://dx.doi.org/10.3390/cancers11040561.
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Background: Colorectal cancer (CRC) is a highly devastating cancer. Ca2+-dependent channels are now considered key regulators of tumor progression. In this study, we aimed to investigate the association of non-voltage gated Ca2+ channels and Ca2+-dependent potassium channels (KCa) with CRC using the transcriptional profile of their genes. Methods: We selected a total of 35 genes covering KCa channels KCNN1–4, KCNMA1 and their subunits KCNMB1–4, endoplasmic reticulum (ER) calcium sensors STIM1 and STIM2, Ca2+ channels ORAI1–3 and the family of cation channels TRP (TRPC1–7, TRPA1, TRPV1/2,4–6 and TRPM1–8). We analyzed their expression in two public CRC datasets from The Cancer Genome Atlas (TCGA) and GSE39582. Results: KCNN4 and TRPM2 were induced while KCNMA1 and TRPM6 were downregulated in tumor tissues comparing to normal tissues. In proximal tumors, STIM2 and KCNN2 were upregulated while ORAI2 and TRPM6 were downregulated. ORAI1 decreased in lymph node metastatic tumors. TRPC1 and ORAI3 predicted poor prognosis in CRC patients. Moreover, we found that ORAI3/ORAI1 ratio is increased in CRC progression and predicted poor prognosis. Conclusions: KCa and Ca2+ channels could be important contributors to CRC initiation and progression. Our results provide new insights on KCa and Ca2+ channels remodeling in CRC.
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Sahin, Kazim, Mehmet Tuzcu, Cemal Orhan, Nurhan Sahin, Sara Perez Ojalvo, Sarah Sylla, and James Komorowski. "The Effects of a Novel Magnesium Complex on the Intestinal Magnesium Transporters in HFD Rats." Current Developments in Nutrition 4, Supplement_2 (May 29, 2020): 1683. http://dx.doi.org/10.1093/cdn/nzaa063_081.
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Abstract Objectives Magnesium (Mg) is absorbed mainly in the intestine and regulates many physiological processes and signaling pathways. TRPM6, a member of the transient receptor potential melastatin-related (TRPM) protein family, is essential for maintaining the organismal Mg2 + balance in the intestine. This study was done to compare the effects of a new form of magnesium, Mg-N21, to magnesium oxide (MgO) on the expression of intestinal Mg transporters in rats Methods Forty-two male Wistar rats (age: 8-week) were randomly divided into the following groups (n = 7 per group): 1) Control; 2) MgO; 3) Mg-N21; 4) HFD (high fat diet); 5) HFD + MgO; 6) HFD + Mg-N21. Magnesium was dosed at 500 milligrams of elemental Mg/kg diet. All rats were supplemented for 8 weeks. Results HFD intake showed a trend toward decreased ileum TRPM6 expression in rats. However, Mg treatment increased ileum TRPM6 expression in HFD rats. TRPM7 expression was not significantly changed. In addition, claudins (Cldn-12 and −15) expression decreased in the ileum of rats fed a HFD. The expressions of ileum claudins were enhanced in Mg-treated rats. The effectiveness of Mg as Mg-21 was more pronounced than Mg as MgO, which can be associated with higher bioavailability. Conclusions Results of the present study show that Mg-N21 is more protective than magnesium oxide on the Mg transporters in rats fed HFD. Funding Sources JDS Therapeutics, LLC Turkish Academy of Sciences.
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Gwanyanya, Asfree, Inga Andriulė, Bogdan M. Istrate, Farjana Easmin, Kanigula Mubagwa, and Regina Mačianskienė. "Modulation of the Cardiac Myocyte Action Potential by the Magnesium-Sensitive TRPM6 and TRPM7-like Current." International Journal of Molecular Sciences 22, no. 16 (August 14, 2021): 8744. http://dx.doi.org/10.3390/ijms22168744.
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The cardiac Mg2+-sensitive, TRPM6, and TRPM7-like channels remain undefined, especially with the uncertainty regarding TRPM6 expression in cardiomyocytes. Additionally, their contribution to the cardiac action potential (AP) profile is unclear. Immunofluorescence assays showed the expression of the TRPM6 and TRPM7 proteins in isolated pig atrial and ventricular cardiomyocytes, of which the expression was modulated by incubation in extracellular divalent cation-free conditions. In patch clamp studies of cells dialyzed with solutions containing zero intracellular Mg2+ concentration ([Mg2+]i) to activate the Mg2+-sensitive channels, raising extracellular [Mg2+] ([Mg2+]o) from the 0.9-mM baseline to 7.2 mM prolonged the AP duration (APD). In contrast, no such effect was observed in cells dialyzed with physiological [Mg2+]i. Under voltage clamp, in cells dialyzed with zero [Mg2+]i, depolarizing ramps induced an outward-rectifying current, which was suppressed by raising [Mg2+]o and was absent in cells dialyzed with physiological [Mg2+]i. In cells dialyzed with physiological [Mg2+]i, raising [Mg2+]o decreased the L-type Ca2+ current and the total delayed-rectifier current but had no effect on the APD. These results suggest a co-expression of the TRPM6 and TRPM7 proteins in cardiomyocytes, which are therefore the molecular candidates for the native cardiac Mg2+-sensitive channels, and also suggest that the cardiac Mg2+-sensitive current shortens the APD, with potential implications in arrhythmogenesis.
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YALÇIN, Emre. "Is there any difference between endometrial hyperplasia and endometrial carcinoma in terms of expression of TRPM2 and TRPM7 ion channels?" TURKISH JOURNAL OF MEDICAL SCIENCES 49, no. 2 (April 18, 2019): 653–60. http://dx.doi.org/10.3906/sag-1810-176.
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De Clercq, Katrien, Vicente Pérez-García, Rieta Van Bree, Federica Pollastro, Karen Peeraer, Thomas Voets, and Joris Vriens. "Mapping the expression of transient receptor potential channels across murine placental development." Cellular and Molecular Life Sciences 78, no. 11 (April 21, 2021): 4993–5014. http://dx.doi.org/10.1007/s00018-021-03837-3.
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AbstractTransient receptor potential (TRP) channels play prominent roles in ion homeostasis by their ability to control cation influx. Mouse placentation is governed by the processes of trophoblast proliferation, invasion, differentiation, and fusion, all of which require calcium signaling. Although certain TRP channels have been shown to contribute to maternal–fetal transport of magnesium and calcium, a role for TRP channels in specific trophoblast functions has been disregarded. Using qRT-PCR and in situ hybridisation, the spatio-temporal expression pattern of TRP channels in the mouse placenta across gestation (E10.5–E18.5) was assessed. Prominent expression was observed for Trpv2, Trpm6, and Trpm7. Calcium microfluorimetry in primary trophoblast cells isolated at E14.5 of gestation further revealed the functional activity of TRPV2 and TRPM7. Finally, comparing TRP channels expression in mouse trophoblast stem cells (mTSCs) and mouse embryonic stem cells (mESC) confirmed the specific expression of TRPV2 during placental development. Moreover, TRP channel expression was similar in mTSCs compared to primary trophoblasts and validate mTSC as a model to study TRP channels in placental development. Collectivity, our results identify a specific spatio-temporal TRP channel expression pattern in trophoblasts, suggesting a possible involvement in regulating the process of placentation.
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Yee, Nelson S., Ada S. Chan, Julian D. Yee, and Rosemary K. Yee. "TRPM7 and TRPM8 Ion Channels in Pancreatic Adenocarcinoma: Potential Roles as Cancer Biomarkers and Targets." Scientifica 2012 (2012): 1–8. http://dx.doi.org/10.6064/2012/415158.
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Transient receptor potential (TRP) ion channels are essential for normal functions and health by acting as molecular sensors and transducing various stimuli into cellular and physiological responses. Growing evidence has revealed that TRP ion channels play important roles in a wide range of human diseases, including malignancies. In light of recent discoveries, it has been found that TRP melastatin-subfamily members, TRPM7 and TRPM8, are required for normal and cancerous development of exocrine pancreas. We are currently investigating the mechanisms which mediate the functional roles of TRPM7 and TRPM8 and attempting to develop these ion channels as clinical biomarkers and therapeutic targets for achieving the goal of personalized therapy in pancreatic cancer.
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Crawley, Scott W., and Graham P. Côté. "Identification of dimer interactions required for the catalytic activity of the TRPM7 alpha-kinase domain." Biochemical Journal 420, no. 1 (April 28, 2009): 115–22. http://dx.doi.org/10.1042/bj20081405.
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TRPM7 (transient receptor potential melastatin) combines an ion channel domain with a C-terminal protein kinase domain that belongs to the atypical alpha-kinase family. The TRPM7 alpha-kinase domain assembles into a dimer through the exchange of an N-terminal segment that extends from residue 1551 to residue 1577 [Yamaguchi, Matsushita, Nairn and Kuriyan (2001) Mol. Cell 7, 1047–1057]. Here, we show, by analysis of truncation mutants, that residues 1553–1562 of the N-terminus are essential for kinase activity but not dimer formation. Within this ‘activation sequence’, site-directed mutagenesis identified Tyr-1553 and Arg-1558 as residues critical for activity. Examination of the TRPM7 kinase domain structure suggests that the activation sequence interacts with the other subunit to help position a catalytic loop that contains the invariant Asp-1765 residue. Residues 1563–1570 of the N-terminal segment are critical for dimer assembly. Mutation of Leu-1564, Ile-1568 or Phe-1570 to alanine abolished both kinase activity and dimer formation. The activity of a monomeric TRPM7 kinase domain lacking the entire N-terminal segment was rescued by a GST (glutathione transferase) fusion protein containing residues 1548–1576 of TRPM7, showing that all interactions essential for activity are provided by the N-terminal segment. Activity was also restored by GST fused to the N-terminal segment of TRPM6 (residues 1711–1740), demonstrating the feasibility of forming functional TRPM6–TRPM7 alpha-kinase domain heterodimers. It is proposed that covalent modifications or binding interactions that alter the conformation of the N-terminal exchanged segment may provide a means to regulate TRPM7 kinase activity.
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Kim, Yu Shin, Eunchai Kang, Yuichi Makino, Sungjin Park, Jung Hoon Shin, Hongjun Song, Pierre Launay, and David J. Linden. "Characterizing the conductance underlying depolarization-induced slow current in cerebellar Purkinje cells." Journal of Neurophysiology 109, no. 4 (February 15, 2013): 1174–81. http://dx.doi.org/10.1152/jn.01168.2011.
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Brief strong depolarization of cerebellar Purkinje cells produces a slow inward cation current [depolarization-induced slow current (DISC)]. Previous work has shown that DISC is triggered by voltage-sensitive Ca influx in the Purkinje cell and is attenuated by blockers of vesicular loading and fusion. Here, we have sought to characterize the ion channel(s) underlying the DISC conductance. While the brief depolarizing steps that triggered DISC were associated with a large Ca transient, the onset of DISC current corresponded only with the Ca transient decay phase. Furthermore, substitution of external Na with the impermeant cation N-methyl-d-glucamine produced a complete and reversible block of DISC, suggesting that the DISC conductance was not Ca permeant. Transient receptor potential cation channel, subfamily M, members 4 (TRPM4) and 5 (TRPM5) are nonselective cation channels that are opened by Ca transients but do not flux Ca. They are expressed in Purkinje cells of the posterior cerebellum, where DISC is large, and, in these cells, DISC is strongly attenuated by nonselective blockers of TRPM4/5. However, measurement of DISC currents in Purkinje cells derived from TRPM4 null, TRPM5 null, and double null mice as well as wild-type mice with TRPM4 short hairpin RNA knockdown showed a partial attenuation with 35–46% of current remaining. Thus, while the DISC conductance is Ca triggered, Na permeant, and Ca impermeant, suggesting a role for TRPM4 and TRPM5, these ion channels are not absolutely required for DISC.
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Hirota, Chieko, Yui Takashina, Yuta Yoshino, Hajime Hasegawa, Ema Okamoto, Toshiyuki Matsunaga, and Akira Ikari. "Reactive Oxygen Species Downregulate Transient Receptor Potential Melastatin 6 Expression Mediated by the Elevation of miR-24-3p in Renal Tubular Epithelial Cells." Cells 10, no. 8 (July 26, 2021): 1893. http://dx.doi.org/10.3390/cells10081893.
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Background: A low level of serum magnesium ion (Mg2+) is associated with type 2 diabetes mellitus (T2D). However, the molecular mechanism of Mg2+ deficiency has not been fully clarified. The current study sought to assesses the effect of reactive oxygen species on the expression of Mg2+ channels and miRNA. Methods: The expression of Mg2+ channels and miRNA were examined by real-time polymerase chain reaction. Intracellular Mg2+ concentration was measured by Magnesium Green fluorescence measurement. Results: The mRNA level of transient receptor potential melastatin 6 (TRPM6), which functions as Mg2+ influx channel in the distal convoluted tubule (DCT) of the kidney, was decreased by glycated albumin (GA), but not by insulin in rat renal tubule-derived NRK-52E cells. The mRNA levels of TRPM7, a homologue of TRPM6, and CNNM2, a Mg2+ efflux transporter located at the basolateral membrane of DCT, were changed by neither GA nor insulin. The generation of reactive oxygen species (ROS) was increased by GA. Hydrogen peroxide (H2O2) dose-dependently decreased TRPM6 mRNA, but it inversely increased the reporter activity of TRPM6. H2O2 accelerated the degradation of TRPM6 mRNA in actinomycin D assay without affecting TRPM7 and CNNM2 mRNA expressions. Nine miRNAs were considered as candidates for the regulator of stability of TRPM6 mRNA. Among them, miR-24-3p expression was increased by H2O2. The H2O2-induced reduction of TRPM6 mRNA was rescued by miR-24-3p siRNA. Magnesium Green fluorescence measurement showed that Mg2+ influx is suppressed by H2O2, which was rescued by an antioxidant and miR-24-3p siRNA. Conclusions: We suggest that GA decreases TRPM6 expression mediated by the elevation of ROS and miR-24-3p in renal tubular epithelial cells of T2D.
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Yu, Weiqun, Warren G. Hill, Gerard Apodaca, and Mark L. Zeidel. "Expression and distribution of transient receptor potential (TRP) channels in bladder epithelium." American Journal of Physiology-Renal Physiology 300, no. 1 (January 2011): F49—F59. http://dx.doi.org/10.1152/ajprenal.00349.2010.
Full textAbstract:
The urothelium is proposed to be a sensory tissue that responds to mechanical stress by undergoing dynamic membrane trafficking and neurotransmitter release; however, the molecular basis of this function is poorly understood. Transient receptor potential (TRP) channels are ideal candidates to fulfill such a role as they can sense changes in temperature, osmolarity, and mechanical stimuli, and several are reported to be expressed in the bladder epithelium. However, their complete expression profile is unknown and their cellular localization is largely undefined. We analyzed expression of all 33 TRP family members in mouse bladder and urothelium by RT-PCR and found 22 specifically expressed in the urothelium. Of the latter, 10 were chosen for closer investigation based on their known mechanosensory or membrane trafficking functions in other cell types. Western blots confirmed urothelial expression of TRPC1, TRPC4, TRPV1, TRPV2, TRPV4, TRPM4, TRPM7, TRPML1, and polycystins 1 and 2 (PKD1 and PKD2) proteins. We further defined the cellular and subcellular localization of all 10 TRP channels. TRPV2 and TRPM4 were prominently localized to the umbrella cell apical membrane, while TRPC4 and TRPV4 were identified on their abluminal surfaces. TRPC1, TRPM7, and TRPML1 were localized to the cytoplasm, while PKD1 and PKD2 were expressed on the apical and basolateral membranes of umbrella cells as well as in the cytoplasm. The cellular location of TRPV1 in the bladder has been debated, but colocalization with neuronal marker calcitonin gene-related peptide indicated clearly that it is present on afferent neurons that extend into the urothelium, but may not be expressed by the urothelium itself. These findings are consistent with the hypothesis that the urothelium acts as a sentinel and by expressing multiple TRP channels it is likely it can detect and presumably respond to a diversity of external stimuli and suggest that it plays an important role in urothelial signal transduction.
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Jimenez, Ivanka, Yolanda Prado, Felipe Marchant, Carolina Otero, Felipe Eltit, Claudio Cabello-Verrugio, Oscar Cerda, and Felipe Simon. "TRPM Channels in Human Diseases." Cells 9, no. 12 (December 4, 2020): 2604. http://dx.doi.org/10.3390/cells9122604.
Full textAbstract:
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.
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Ledeganck, Kristien J., Gaëlle A. Boulet, Caroline A. Horvath, Marleen Vinckx, Johannes J. Bogers, Rita Van Den Bossche, Gert A. Verpooten, and Benedicte Y. De Winter. "Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment." American Journal of Physiology-Renal Physiology 301, no. 3 (September 2011): F486—F493. http://dx.doi.org/10.1152/ajprenal.00116.2011.
Full textAbstract:
Renal magnesium (Mg2+) and sodium (Na+) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg2+ reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thébault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78–85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na+-Cl− cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg2+ (FE Mg2+) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg2+ in CsA-treated rats. These data suggest that CsA treatment affects Mg2+ homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss.
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Lam, D. Hung, Caroline E. Grant, and Ceredwyn E. Hill. "Differential expression of TRPM7 in rat hepatoma and embryonic and adult hepatocytes." Canadian Journal of Physiology and Pharmacology 90, no. 4 (April 2012): 435–44. http://dx.doi.org/10.1139/y11-136.
Full textAbstract:
TRPM7 channels are implicated in cellular survival, proliferation, and differentiation. However, a profile of TRPM7 activity in a specific cell type has not been determined from embryonic to terminally differentiated state. Here, we characterized TRPM7 expression in a spectrum of rat liver cells at different developmental stages. Using the whole-cell patch clamp technique, TRPM7-like Na+ currents were identified in RLC-18 cells, a differentiated, proliferating hepatocellular line derived from day 17 embryonic rat liver. Currents were outwardly rectifying, enhanced in divalent-free solutions, and inhibited by intracellular Mg2+. Reverse transcription – polymerase chain reaction (RT–PCR) revealed that RLC-18 cells express both TRPM6 and TRPM7. However, mean currents were reduced almost 80% by 1 mmol/L 2-aminoethoxyphenylborate (2-APB) and were abolished in RLC-18 cells heterologously expressing a dominant negative TRPM7 construct, suggesting that TRPM7 is the major current carrier in these cells. Functional comparison showed that relative to terminally differentiated adult rat hepatocytes, currents were 1.8 and 3.9 times higher in, respectively, RLC-18 and WIF-B cells, a rat hepatoma – human fibroblast cross. Our results demonstrate that plasma membrane TRPM7 channels are more highly expressed in proliferating cells as compared with terminally differentiated and nondividing rat hepatocytes and suggest that downregulation of this channel is associated with hepatocellular differentiation.
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Yin, Ying, Mengyu Wu, Lejla Zubcevic, William F. Borschel, Gabriel C. Lander, and Seok-Yong Lee. "Structure of the cold- and menthol-sensing ion channel TRPM8." Science 359, no. 6372 (December 7, 2017): 237–41. http://dx.doi.org/10.1126/science.aan4325.
Full textAbstract:
Transient receptor potential melastatin (TRPM) cation channels are polymodal sensors that are involved in a variety of physiological processes. Within the TRPM family, member 8 (TRPM8) is the primary cold and menthol sensor in humans. We determined the cryo–electron microscopy structure of the full-length TRPM8 from the collared flycatcher at an overall resolution of ~4.1 ångstroms. Our TRPM8 structure reveals a three-layered architecture. The amino-terminal domain with a fold distinct among known TRP structures, together with the carboxyl-terminal region, forms a large two-layered cytosolic ring that extensively interacts with the transmembrane channel layer. The structure suggests that the menthol-binding site is located within the voltage-sensor–like domain and thus provides a structural glimpse of the design principle of the molecular transducer for cold and menthol sensation.
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Thiel, Gerald, and Oliver G. Rössler. "Expression of the C-Terminal Domain of Phospholipase Cβ3 Inhibits Signaling via Gαq-Coupled Receptors and Transient Receptor Potential Channels." International Journal of Molecular Sciences 23, no. 17 (August 24, 2022): 9590. http://dx.doi.org/10.3390/ijms23179590.
Full textAbstract:
Transient receptor potential (TRP) channels are cation channels that play a regulatory role in pain and thermosensation, insulin secretion, and neurotransmission. It has been proposed that activation of TRP channels requires phosphatidylinositol 4,5-bisphosphate, the major substrate for phospholipase C (PLC). We investigated whether inhibition of PLCβ has an impact on TRP channel signaling. A genetic approach was used to avoid off-target effects observed when using a pharmacological PLCβ inhibitor. In this study, we show that expression of PLCβct and PLCβ3ct, truncated forms of PLCβ1 or PLCβ3 that contain the C-terminal membrane binding domains, almost completely blocked the signal transduction of a Gαq-coupled designer receptor, including the phosphorylation of ERK1/2. In contrast, expression of the helix-turn-helix motif (Hα1-Hα2) of the proximal C-terminal domain of PLCβ3 did not affect Gαq-coupled receptor signaling. PLCβ3ct expression impaired signaling of the TRP channels TRPM3 and TRPM8, stimulated with either prognenolone sulfate or icilin. Thus, the C-terminal domain of PLCβ3 interacts with plasma membrane targets, most likely phosphatidylinositol 4,5-bisphosphate, and in this way blocks the biological activation of TRPM3 and TRPM8, which require interaction with this phospholipid. PLCβ thus regulates TRPM3 and TRPM8 channels by masking phosphatidylinositol 4,5-bisphosphate with its C-terminal domain.
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Song, Yumei, Ben Buelow, Anne-Laure Perraud, and Andrew M. Scharenberg. "Development and Validation of a Cell-Based High-Throughput Screening Assay for TRPM2 Channel Modulators." Journal of Biomolecular Screening 13, no. 1 (November 26, 2007): 54–61. http://dx.doi.org/10.1177/1087057107310986.
Full textAbstract:
TRPM2 is a member of the transient receptor potential melastatin (TRPM)—related ion channel family. The activation of TRPM2 induced by oxidative/nitrosative stress leads to an increase in intracellular free Ca2+. Although further progress in understanding TRPM2's role in cell and organism physiology would be facilitated by isolation of compounds able to specifically modulate its function in primary cells or animal models, no cell-based assays for TRPM2 function well suited for high-throughput screening have yet been described. Here, a novel suspension B lymphocyte cell line stably expressing TRPM2 was used to develop a cell-based assay. The assay uses the Ca2+-sensitive fluorescence dye, Fluo-4 NW (no wash), to measure TRPM2-dependent Ca2+ transients induced by H2O2 and N-methyl-N′-nitrosoguanidine in a 96-well plate format. Assay performance was evaluated by statistical analysis of the Z′ factor value and was consistently greater than 0.5 under optimal conditions, suggesting that the assay is very robust. For assay validation, the effects of known inhibitors of TRPM2 and TRPM2 gating secondary messenger production were determined. Overall, the authors have developed a cell-based assay that may be used to identify TRPM2 ion channel modulators from large compound libraries. ( Journal of Biomolecular Screening 2008:54-61)
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Kim, Byung Joo, Sung-Young Kim, Sanghoon Lee, Ju-Hong Jeon, Hirofumi Matsui, Young Kyu Kwon, Seon Jeong Kim, and Insuk So. "The role of transient receptor potential channel blockers in human gastric cancer cell viability." Canadian Journal of Physiology and Pharmacology 90, no. 2 (February 2012): 175–86. http://dx.doi.org/10.1139/y11-114.
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Transient receptor potential cation channel, subfamily M, receptor 7 (TRPM7) is a ubiquitous divalent-selective ion channel with its own kinase domain. Human gastric cancer cells express the TRPM7 channel, and the presence of this channel is essential for cell survival. Recent studies have suggested that 5-lipoxygenase (5-LOX) inhibitors are potent blockers of the TRPM7 channels. The aim of this study was to show the effects of 5-LOX inhibitors on the growth and survival of gastric cancer cells. Among 5-LOX inhibitors, nordihydroguaiaretic acid (NDGA), 2,3,5-trimethyl-6-(12-hydroxy-5,10-dodecadiynyl)-1,4-benzoquinone (AA861), and 3-[1-(p-chlorobenzyl)-5-(isopropyl)-3-tert-butylthioindol-2-yl]-2,2-dimethylpropanoic acid (MK886) were potent blockers of TRPM7-like currents in gastric cancer cells and also induced cell death. However, zileuton was ineffective in suppressing TRPM7-like current activity and inducing cell death. Moreover, a specific transient receptor potential cation channel, subfamily C, member 3 (TRPC3) inhibitor, a pyrazole compound (Pyr3), and a specific melastatin TRP (TRPM4) inhibitor, 9-phenanthrol, did not affect TRPM7-like currents or induce cell death. We conclude that TRPM7 has an important role in the growth and survival of gastric cancer cells and a likely potential target for the pharmacological treatment of gastric cancer.
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Balemans, Dafne, Guy E. Boeckxstaens, Karel Talavera, and Mira M. Wouters. "Transient receptor potential ion channel function in sensory transduction and cellular signaling cascades underlying visceral hypersensitivity." American Journal of Physiology-Gastrointestinal and Liver Physiology 312, no. 6 (June 1, 2017): G635—G648. http://dx.doi.org/10.1152/ajpgi.00401.2016.
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Visceral hypersensitivity is an important mechanism underlying increased abdominal pain perception in functional gastrointestinal disorders including functional dyspepsia, irritable bowel syndrome, and inflammatory bowel disease in remission. Although the exact pathophysiological mechanisms are poorly understood, recent studies described upregulation and altered functions of nociceptors and their signaling pathways in aberrant visceral nociception, in particular the transient receptor potential (TRP) channel family. A variety of TRP channels are present in the gastrointestinal tract (TRPV1, TRPV3, TRPV4, TRPA1, TRPM2, TRPM5, and TRPM8), and modulation of their function by increased activation or sensitization (decreased activation threshold) or altered expression in visceral afferents have been reported in visceral hypersensitivity. TRP channels directly detect or transduce osmotic, mechanical, thermal, and chemosensory stimuli. In addition, pro-inflammatory mediators released in tissue damage or inflammation can activate receptors of the G protein-coupled receptor superfamily leading to TRP channel sensitization and activation, which amplify pain and neurogenic inflammation. In this review, we highlight the present knowledge on the functional roles of neuronal TRP channels in visceral hypersensitivity and discuss the signaling pathways that underlie TRP channel modulation. We propose that a better understanding of TRP channels and their modulators may facilitate the development of more selective and effective therapies to treat visceral hypersensitivity.