TRPM2: a multifunctional ion channel for calcium signalling (original) (raw)
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The transient receptor potential melastatin-2 (TRPM2) channel and inflammation
Inflammation is an early mechanism of the immune system to eliminate pathogens and to repair damaged tissue. However, unregulated and persistent inflammation can lead to chronic inflammatory diseases. The transient receptor potential melastatin-2 (TRPM2) channel, a calcium (Ca2+)-permeable channel containing intracellular adenosine diphosphate ribose (ADPR) pyrohydrolase activity, has recently been identified as a critical molecular mechanism in reactive oxygen species (ROS)-induced inflammatory process, and thereby, emerged as a potential target for therapeutic intervention. ADPR biding to TRPM2 Nudix-like domain (or NUDT9 homology domain) results in the channel pore opening allowing lysosomal Ca2+ release and Ca2+ influx into the cells. Ca2+ influx via TRPM2 controls ROS-induced nuclear translocation of NF-κB and CXCL2 production in monocytes during inflammation in a chronic experimental colitis mouse model. Moreover, TRPM2 deficient-dendritic cells show defective Ca2+ signals and...
TRPM2 Channel-Mediated ROS-Sensitive Ca(2+) Signaling Mechanisms in Immune Cells
Frontiers in immunology, 2015
Transient receptor potential melastatin 2 (TRPM2) proteins form Ca(2+)-permeable cationic channels that are potently activated by reactive oxygen species (ROS). ROS are produced during immune responses as signaling molecules as well as anti-microbial agents. ROS-sensitive TRPM2 channels are widely expressed in cells of the immune system and located on the cell surface as a Ca(2+) influx pathway in macrophages, monocytes, neutrophils, lymphocytes, and microglia but preferentially within the lysosomal membranes as a Ca(2+) release mechanism in dendritic cells; ROS activation of the TRPM2 channels, regardless of the subcellular location, results in an increase in the intracellular Ca(2+) concentrations. Recent studies have revealed that TRPM2-mediated ROS-sensitive Ca(2+) signaling mechanisms play a crucial role in a number of processes and functions in immune cells. This mini-review discusses the recent advances in revelation of the various roles the TRPM2 channels have in immune cell...
TRPM2 functions as a lysosomal Ca2+-release channel in beta cells
Science signaling, 2009
TRPM2 is a Ca2+-permeable cation channel that is specifically activated by adenosine diphosphoribose (ADPR). Channel activation in the plasma membrane leads to Ca2+ influx and has been linked to apoptotic mechanisms. The primary agonist, ADPR, is produced both extra- and intracellularly and causes increases in intracellular calcium concentration ([Ca2+]i), but the mechanisms involved are not understood. Using short interfering RNA and a knockout mouse, we report that TRPM2, in addition to its role as a plasma membrane channel, also functions as a Ca2+-release channel activated by intracellular ADPR in a lysosomal compartment. We show that both functions of TRPM2 are critically linked to hydrogen peroxide-induced beta cell death. Additionally, extracellular ADPR production by the ectoenzyme CD38 from its substrates NAD+ (nicotinamide adenine dinucleotide) or cADPR causes IP3-dependent Ca2+ release via P2Y and adenosine receptors. Thus, ADPR and TRPM2 represent multimodal signaling el...
Cell Communication and Signaling
The transient receptor potential melastatin subfamily member 2 (TRPM2), a thermo and reactive oxygen species (ROS) sensitive Ca2+-permeable cation channel has a vital role in surviving the cell as well as defending the adaptability of various cell groups during and after oxidative stress. It shows higher expression in several cancers involving breast, pancreatic, prostate, melanoma, leukemia, and neuroblastoma, indicating it raises the survivability of cancerous cells. In various cancers including gastric cancers, and neuroblastoma, TRPM2 is known to conserve viability, and several underlying mechanisms of action have been proposed. Transcription factors are thought to activate TRPM2 channels, which is essential for cell proliferation and survival. In normal physiological conditions with an optimal expression of TRPM2, mitochondrial ROS is produced in optimal amounts while regulation of antioxidant expression is carried on. Depletion of TRPM2 overexpression or activity has been show...
Cellular Signalling, 2013
The transient receptor potential melastatin (TRPM) protein family is an extensive group of ion channels expressed in several types of mammalian cells. Many studies have shown that these channels are crucial for performing several physiological functions. Additionally, a large body of evidence indicates that these channels are also involved in numerous human diseases, known as channelopathies. A characteristic event frequently observed during pathological states is the raising in intracellular oxidative agents over reducing molecules, shifting the redox balance and inducing oxidative stress. In particular, three members of the TRPM subfamily, TRPM2, TRPM4 and TRPM7, share the remarkable feature that their activities are modulated by oxidative stress. Because of the increase in oxidative stress, these TRPM channels function aberrantly, promoting the onset and development of diseases. Increases, absences, or modifications in the function of these redox-modulated TRPM channels are associated with cell dysfunction and human pathologies. Therefore, the effect of oxidative stress on ion channels becomes an essential part of the pathogenic mechanism. Thus, oxidative stress-modulated ion channels are more susceptible to generating pathological states than oxidant-independent channels. This review examines the most relevant findings regarding the participation of the oxidative stress-modulated TRPM ion channels, TRPM2, TRPM4, and TRPM7, in human diseases. In addition, the potential roles of these channels as therapeutic tools and targets for drug design are discussed.
TRPM channels as potential therapeutic targets against pro-inflammatory diseases
Cell calcium, 2017
The immune system protects our body against foreign pathogens. However, if it overshoots or turns against itself, pro-inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, or diabetes develop. Ions, the most basic signaling molecules, shape intracellular signaling cascades resulting in immune cell activation and subsequent immune responses. Mutations in ion channels required for calcium signaling result in human immunodeficiencies and highlight those ion channels as valued targets for therapies against pro-inflammatory diseases. Signaling pathways regulated by melastatin-like transient receptor potential (TRPM) cation channels also play crucial roles in calcium signaling and leukocyte physiology, affecting phagocytosis, degranulation, chemokine and cytokine expression, chemotaxis and invasion, as well as lymphocyte development and proliferation. Therefore, this review discusses their regulation, possible interactions and whether they can be exploited as ta...
Role of TRPM2 in cell proliferation and susceptibility to oxidative stress
American Journal of Physiology-Cell Physiology, 2013
The transient receptor potential (TRP) channel TRPM2 is an ion channel that modulates cell survival. We report here that full-length (TRPM2-L) and short (TRPM2-S) isoform expression was significantly increased in human neuroblastoma compared with adrenal gland. To differentiate the roles of TRPM2-L and TRPM2-S in cell proliferation and survival, we established neuroblastoma SH-SY5Y cell lines stably expressing either TRPM2 isoform or empty vector. Cells expressing TRPM2-S showed significantly enhanced proliferation, downregulation of phosphatase and tensin homolog (PTEN), and increased protein kinase B (Akt) phosphorylation and cell surface glucose transporter 1 (Glut1) compared with cells expressing TRPM2-L or empty vector. ERK phosphorylation was increased, and forkhead box O 3a (FOXO3a) levels were decreased. Inhibitor studies demonstrated that enhanced proliferation was dependent on phosphatidylinositol 3-kinase/Akt, ERK, and NADPH oxidase activation. On the other hand, TRPM2-S-...
British Journal of Pharmacology, 2004
1 TRPM2 (melastatin-like transient receptor potential 2 channel) is a nonselective cation channel that is activated under conditions of oxidative stress leading to an increase in intracellular free Ca 2 þ concentration ([Ca 2 þ ] i ) and cell death. We investigated the role of the DNA repair enzyme poly(ADPribose) polymerase (PARP) on hydrogen peroxide (H 2 O 2 )-mediated TRPM2 activation using a tetracycline-inducible TRPM2-expressing cell line.
Pharmaceuticals, 2021
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 wel...