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Abstract Transient receptor potential melastatin 2 (TRPM2) assembles into tetramers to function as an oxidative stress‐sensitive Ca 2+ channel at the surface membrane. Limited information is currently available on the 10 protein isoforms of mouse TRPM2 ( m TRPM2) identified. This study investigated whether these isoforms function as Ca 2+ channels and examined their effects on full‐length m TRPM2 activity using the HEK 293 cell exogenous expression system. Only full‐length m TRPM2, isoform 1 localized to the surface membrane and was activated by oxidative stress. Isoform 7 was clearly recognized by protein quality control systems and degraded by endoplasmic reticulum‐associated degradation after transmembrane proteolysis. In the co‐expression system, the activation and expression of full‐length m TRPM2 were attenuated by its co‐expression with isoform 7, but not with the other isoforms. This decrease in the expression of full‐length m TRPM2 was recovered by the proteasomal inhibitor. The present results suggest that isoforms other than isoform 1 did not function as oxidative stress‐sensitive channels and also that only isoform 7 attenuated the activation of full‐length m TRPM2 by targeting it to endoplasmic reticulum‐associated degradation. The present study will provide important information on the functional nature of m TRPM2 isoforms for the elucidation of their roles in physiological and patho‐physiological responses in vivo using mouse models.Keywords:
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The transient receptor potential (TRP) family includes cation-permeable ion channels activated by diverse stimuli ranging from chemical compounds, mechanical force and temperature. TRPA1, TRPV1, TRPC5, TRPM2, and TRPM7 are reported to be activated by reactive oxygen species (ROS). The sensitivity of TRPs to ROS is in part associated with pathogenesis caused by ROS and physiological adaptations to redox signals. The present review focuses on the well-defined ROS-sensitive TRP channels, TRPA1 and TRPM2, and summarizes recent reports regarding their activation mechanism by ROS and their relevance to pathological conditions and physiological functions in which ROS are involved.
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The transient receptor potential melastatin (TRPM) family belongs to the superfamily of TRP ion channels. It consists of eight family members that are involved in a plethora of cellular functions. TRPM2 is a homotetrameric Ca2+-permeable cation channel activated upon oxidative stress and is important, among others, for body heat control, immune cell activation and insulin secretion. Invertebrate TRPM2 proteins are channel enzymes; they hydrolyze the activating ligand, ADP-ribose, which is likely important for functional regulation. Since its cloning in 1998, the understanding of the biophysical properties of the channel has greatly advanced due to a vast number of structure–function studies. The physiological regulators of the channel have been identified and characterized in cell-free systems. In the wake of the recent structural biochemistry revolution, several TRPM2 cryo-EM structures have been published. These structures have helped to understand the general features of the channel, but at the same time have revealed unexplained mechanistic differences among channel orthologues. The present review aims at depicting the major research lines in TRPM2 structure-function. It discusses biophysical properties of the pore and the mode of action of direct channel effectors, and interprets these functional properties on the basis of recent three-dimensional structural models.
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The transient potential receptor melastatin-2 (TRPM2) channel has emerged as an important Ca(2+) signalling mechanism in a variety of cells, contributing to cellular functions that include cytokine production, insulin release, cell motility and cell death. Its ability to respond to reactive oxygen species has made TRPM2 a potential therapeutic target for chronic inflammation, neurodegenerative diseases, and oxidative stress-related pathologies. TRPM2 is a non-selective, calcium (Ca(2+))-permeable cation channel of the melastatin-related transient receptor potential (TRPM) ion channel subfamily. It is activated by intracellular adenosine diphosphate ribose (ADPR) through a diphosphoribose hydrolase domain in its C-terminus and regulated through a variety of factors, including synergistic facilitation by [Ca(2+)](i), cyclic ADPR, H(2)O(2), NAADP, and negative feedback regulation by AMP and permeating protons (pH). In addition to its role mediating Ca(2+) influx into the cells, TRPM2 can also function as a lysosomal Ca(2+) release channel, contributing to cell death. The physiological and pathophysiological context of ROS-mediated events makes TRPM2 a promising target for the development of therapeutic tools of inflammatory and degenerative diseases.
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Cationic channels of the TRP melastatin family are involved in pigmentation and oxidative stress responses.
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Transient receptor potential (TRP) proteins have been implicated in several cell functions as non-selective cation channels, with about 30 different mammalian TRP channels having been recognized. Among them, TRP-melastatin 2 (TRPM2) is particularly involved in the response to oxidative stress and inflammation, while its activity depends on the presence of intracellular calcium (Ca2+). TRPM2 is involved in several physiological and pathological processes in the brain through the modulation of multiple signaling pathways. The aim of the present review is to provide a brief summary of the current insights of TRPM2 role in health and disease to focalize our attention on future potential neuroprotective strategies.
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Transient receptor potential (TRP) superfamily is a superfamily of cation channels that can be divided into seven subfamilies. TRPM2 is the second member of the TRPM subfamily, which includes eight members, namely TRPM1-8. TRPM2 is widely expressed in excitable and non-excitable cells, where it forms a Ca(2+)-permeable cation channel and performs diverse cellular functions. TRPM2 channels are activated by ADP-ribose (ADPR), Ca(2+), H2O2 and other reactive oxygen species (ROS). It is established that TRPM2 serves as a cellular sensor for oxidative stress, mediating oxidative stress-induced [Ca(2+)]i increase and contributing to pathological processes in many cell types. Accumulating evidence has indicated that TRPM2 is a potential therapeutic target for oxidative stress-related diseases. This review will highlight recent progress in this field.
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Transient receptor potential (TRP) channel is a superfamily of cation channels located on the cell membrane. TRP channels are classified into seven subfamilies based on the amino acid sequence homology,and transient receptor potential melastatin 2(TRPM2) is the second member of the TRPM subfamily. More evidences have revealed the important roles of TRPM2 in physiological and pathological events such as release of insulin from pancreatic Β-cells,inflammatory cytokines production from cells,and oxidative stress-induced cell death. As a cellular sensor for oxidative stress channel,TRPM2 is activated by a variety of factors. TRPM2 is a potential therapeutic target for oxidative stress-related diseases.
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Transient receptor potential melastatin 2 (TRPM2) is a calcium-permeable ion channel implicated in neurodegenerative disorders and conditions. It is activated in response to reactive oxygen species (ROS) and thereby alters Ca2+ homeostasis and initiates pathways that lead to apoptosis and cell dysfunction. This review summarizes the current role of TRPM2 in neurological disorders, including Parkinson’s disease, Alzheimer’s disease, ischemia, traumatic brain injury, and depressive disorders (bipolar disease and depression). It describes the distribution and function of the TRPM2 channel across the brain and highlights common mechanisms between diseases. Specific animal and cell culture studies using TRPM2 inhibitors or genetic knockouts are discussed, including strategies to reduce the effect of ROS in disease through TRPM2 inhibition.
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