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Ion Channels in Immune Cells
Published in Shyam S. Bansal, Immune Cells, Inflammation, and Cardiovascular Diseases, 2022
Devasena Ponnalagu, Shridhar Sanghvi, Shyam S. Bansal, Harpreet Singh
TRP channels are present in both the adaptive and the innate immune cells and act as mediators to conduct Ca2+, Mg2+ (TRPM2, TRPM6, TRPM7), and Na+ (TRPM4). As described earlier, the major role of some of the TRP channels is to modulate intracellular Ca2+ in immune cells and, thus, influence their function. They have been established to play a role in phagocytosis, immune cell migration, and the release of inflammatory cytokines. It is known that, following TCR stimulation, TRPM2 channels become activated probably via release of cyclic ADP ribose (ADPR) from the ER, which is involved in their proliferation and pro-inflammatory cytokine secretion59,60. Moreover, TRPM2 deficiency mitigated the development of encephalomyelitis in mice61. TRPM2-mediated Ca2+ signaling was also shown to be involved in the maturation of DCs through modulation of the processing of MHC class II molecules62. The absence of TRPM4 channels in DCs led to impaired migration due to disruption of Ca2+ homeostasis60. In addition, phagocytic activity and cytokine release by macrophages were diminished in TRPM4-deficient mice60. B cells lacking a TRPM7 channel exhibited an inability to proliferate and an increased death rate60. In the case of T cells as well, mice lacking T cell–specific TRPM7 showed a defect in T cell development60. There are also other members of this channel group that have been studied extensively and shown to be important in modulating immune cell function and development and inflammatory diseases60. Due to their key role in immune cell maturation and activation, they are also considered to be a great therapeutic target against autoimmune disorders, like rheumatoid arthritis, type I diabetes, lupus erythematosus, and multiple sclerosis, and thus need to be evaluated clinically.
Ion Channel Conformational Coupling in Ischemic Neuronal Death
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
TRP channels represent a large group of non-selective cation channels conducting not only monovalent cations such as Na+ and K+, but also divalent cations like Ca2+, Zn2+, or Mg2+ to different degrees (Nilius and Owsianik, 2011). The 28 mammalian TRP members are divided into six subfamilies and involved in diverse functions such as sensing temperature, osmotic pressure, or volume changes, and a variety of chemicals (Ramsey et al., 2006). TRP channels play important roles in many physical and pathological processes, such as taste, nociception, and ischemic injuries. Although most TRP channels fulfill their functions by regulating ionic balance across biomembranes, some of them, such as transient receptor potential-melastatin-like 2 (TRPM2), TRPM6, and TRPM7, also function in ion conduction-independent manners (Krapivinsky et al., 2014; Perraud et al., 2001; Riazanova et al., 2001; Runnels et al., 2001; Sano et al., 2001). For instance, TRPM6 and TRPM7 are chanzymes, which not only act as ion channels mediating cation fluxes including Ca2+, Zn2+, and Mg2+, but also contain a serine/threonine kinase domain at the carboxyl terminus (CT) of each subunit. TRPM7 has been considered as a major regulator for cellular Mg2+ homeostasis in vertebrates. However, tissue-specific deletion of the Trpm7 gene from mouse T cells impairs thymopoiesis without affecting either the acute Mg2+ uptake ability or the maintenance of cellular Mg2+ levels (Jin et al., 2008). Instead, syntheses of many essential growth factors are severely disrupted in Trpm7−/− thymocytes, which impairs the differentiation and maintenance of thymic epithelial cells. Therefore, TRPM7 regulates thymopoiesis through its CT kinase activity but not via Mg2+ conducting function. Interestingly, in some specific progenitors derived from mouse embryonic stem cells (mESCs), the TRPM7 kinase domain can be cleaved from the channel part in vivo in a cell type-specific fashion (Krapivinsky et al., 2014). The TRPM7 cleaved kinases (M7CKs) translocate to the nucleus and bind to the zinc-finger domains of multiple chromatin-remodeling complexes, which modify histone phosphorylation (e.g. H3S10, H3S28, and H3T3) to regulate gene expression pattern. This binding is Zn2+ dependent and largely dependent on TRPM7’s Zn2+ conducting function, suggesting a synergistic action of the ionotropic and metabotropic functions of TRPM7. The cleavage-dependent nuclear action of TRPM7 resembles that of Cav1.2 L-type voltage-gated Ca2+ channel, which also regulates gene expression through proteolytic cleavage of its CT and translocation of the cleaved small fragment into nucleus to activate gene transcription in neurons (Gomez-Ospina et al., 2006).
Rituximab Attenuated Lipopolysaccharide-Induced Oxidative Cytotoxicity, Apoptosis, and Inflammation in the Human Retina Cells via Modulating the TRPM2 Signaling Pathways
Published in Ocular Immunology and Inflammation, 2022
Hatice Daldal, Mustafa Nazıroğlu
The whole cell electrophysiology configuration records were obtained in EPC 10 amplifier equipped with Patch-master software (HEKA, Lamprecht, Germany). In the records (n = 4–6), the holding potential (−65 mV) and pipette resistances (3 and 7 MΩ) were kept as described in the previous experiments.4,37 In the records, CaCl2 (1 mM), MgCl2 (1 mM), KCl (5 mM), NaCl (145 mM), D-glucose (10 mM), and HEPES (10 mM) added to the extracellular (patch chamber) solution. For preparing the Na+ free patch chamber solution, we used 150 mM N-methyl-D-glucamine (NMDG+) instead of 145 mM NaCl (pH: 7.4). The cytCa2+ was adjusted to 1 μM instead of 100 nM, when the TRPM2 is gated in the presence of high intracellular cytCa2+.38 The TRPM2 were stimulated in the cells by using the cytosolic ADPR (1 mM in patch pipette), although it was blocked by extracellular ACA (25 μM in patch-chamber). The voltage-clamp results were shown as the current density (pA/pF).
The involvement of TRPM2 on the MPP+-induced oxidative neurotoxicity and apoptosis in hippocampal neurons from neonatal mice: protective role of resveratrol
Published in Neurological Research, 2022
Kenan Yildizhan, Ramazan Çinar, Mustafa Naziroğlu
Considering all the results of our study, the increased ROS and mitochondrial dysfunction in the PD model also play a triggering role in this mechanism. The damage mechanism, which continues with the increase in intracellular OS, especially continues with caspase activation, causing the cells to enter apoptosis. It was observed that TRPM2 channel expression and activation increased along with this mechanism. We think that it is a very important finding that both channel increase and free intracellular Ca2+ ion increase can be blocked with channel antagonists in MPP-induced cells. We found that resveratrol plays an important role by regulating the increased OS level caused by MPP with its antioxidant property, reducing TRPM2 channel activation and preventing further Ca2+ increase into the cell. Our study results showed that in PD disease, in addition to taking antioxidant substances in the regulation of damage to the hippocampus, the use of channel antagonists in TRPM2 channel activation, which is an important pathway in the damage mechanism, can be a therapeutic approach.
Oxidative stress promotes ventilator-induced lung injury through activating NLRP3 inflammasome and TRPM2 channel
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Xiaona An, Xiaotong Sun, Xiaomei Yang, Dejie Liu, Yonghao Hou, Hongli Chen, Jianbo Wu
The transient receptor potential (TRP) channels are important cation channels on the cell membrane, which are permeable to calcium ions. The TRP channels have 6 subfamilies: TRPC, TRPY, TRPM, TRPA, TRPP and TRPML [18,19]. TRPM2 channel is a class of non-selective cation channel of calcium ions, which is highly expressed in the brain tissues [20]. Studies have shown that stimulation of adverse factors such as inflammation, ischemia, and hypoxia could suppress TRPM2 channel, and further enhance the survival of astrocytes [21]. Meanwhile, knockdown of TRPM2 switched cells from cell death to autophagy for survival in response to oxidative stress [22]. In our study, TRPM2 channel currently declined markedly after treatment with NLRP3 siRNA and Caspase-1 siRNA, suggesting that NLRP3 and Caspase-1 play an important role in regulating the TRPM2 channel.