ReviewOxidative stress-modulated TRPM ion channels in cell dysfunction and pathological conditions in humans
Introduction
The transient receptor potential (TRP) protein ion channel family is expressed in several organisms, including worms, drosophila, and mammals [1], [2], [3]. The trp gene was first described by Montell & Rubin using Drosophila-based experiments [4]. The TRP family is divided into six main subfamilies based on their protein sequence homology: canonical (TRPC), vanilloid (TRPV), ankyrin (TRPA), polycystic kidney disease (TRPP), mucolipin (TRPML), and melastatin (TRPM) (Fig. 1). TRP channels have six predicted transmembrane domains and a pore region between the fifth and sixth transmembrane domains (Fig. 2) [5], [6], [7], [8]. These ion channels are involved in several physiological processes, including vessel tone control, sensory perception, proliferation, and cell survival and death [1], [2], [3], [9], [10].
The TRPM subfamily takes its name from the first described member, melastatin (TRPM1), a protein identified as a potential tumor suppressor [11], [12]. Currently, 8 proteins belong to this family. Most members of the TRPM subfamily are Ca2 +-permeable and Ca2 +-activated proteins, often associated with sensory perception systems [13], [14]. However, a large body of evidence has shown that members of this family are involved in additional roles critical for maintaining cellular homeostasis and organ function. Thus, alterations in TRPM ion channel activity will affect physiological functions, prompting the onset of pathological states. Few ion channels have the unique feature of being modulated by oxidative stress at micromolar concentrations [15], [16], [17], [18], [19], [20], [21], [22]. The activity of some members of the TRPM subfamily is modulated by oxidative stress [23]. Specifically, three members of the TRPM subfamily have emerged as the most important oxidative stress-modulated TRPM ion channels: TRPM2, TRPM4, and TRPM7 (Fig. 3). These channels are involved in several normal physiological processes as well as a number of human diseases. Reactive oxygen species (ROS) are able to modify the function of these TRPM channels, producing functional changes, which become imbalances in cellular homeostasis. Consequently, several processes regulated by these channels are modified by oxidative stress generating a pathological phenotype.
Moderate increases in intracellular ROS perform normal cellular functions [24]. However, a large increase in intracellular oxidative stress is a hallmark of several human diseases [24], [25]. Thus, oxidative stress participates in cell proliferation [26], [27], cell volume regulation [27], fibrosis [28], [29], and several other functions.
Because an oxidative environment appears to be a factor in almost all pathologies, the occurrence of oxidative stress-modulated ion channels in an oxidative environment generates a favorable scenario for disease development. In contrast to oxidant-induced protein destruction, with its consequent loss of function, these oxidative-sensitive ion channels respond to oxidant molecules by modifying their function into aberrant behavior, generating pathological states.
In this review, we focused on describing and discussing the relevant studies regarding the involvement of the oxidative stress-modulated ion channels, TRPM2, TRPM4, and TRPM7, in cell dysfunction and human pathology.
Section snippets
TRPM2
The TRPM2 ion channel (also known as LTRPC2 and TrpC7) is permeable to divalent ions such as Ca2 + and Mg2 +, and to monovalent ions, such as Na+ and K+ [30] (Fig. 2). TRPM2 was first cloned by Nagamine and coworkers [31]. Its structure contains an enzymatic region with ADP-ribose (ADPR)-hydrolase activity [32], [33]. TRPM2 is expressed in several cell types, including microglial cells [34], [35], neutrophil granulocytes [36], [37], immune cells [32], [33], insulin-secreting cells [38], [39], [40]
Cellular function impairment, cell death, and human pathological conditions
Although TRPM channels are involved in several human pathologies, we focused here in those which the participation of the stress oxidative-modulated ion channels, TRPM2, TRPM4, and TRPM7, has been demonstrated (Fig. 5). Table 2 summarizes all main findings of the oxidative stress-modulated TRPM ion channels involved in pathological conditions in humans.
Inflammation and immune system activation
Globally, the role of ROS-modulated TRPM2 activity is linked to several inflammatory situations. For instance, in dextran sulfate sodium (DSS)-induced experimental colitis used as an ROS-related inflammation model, TRPM2-knockout (KO) mice show a reduction in several indicators of inflammation, including monocyte activation, neutrophil migration and infiltration, and ulceration [6], [109]. Accordingly, TRPM2-KO mice are extremely vulnerable to infection with Listeria monocytogenes. The innate
Neurodegenerative diseases and neurological disorders
TRPM2 has been linked to several neurodegenerative diseases. Cultured neurons transfected with small interfering RNA against rat TRPM2 are resistant to H2O2-induced neuronal death [118]. Similarly, A172 glioblastoma cells stably-transfected with TRPM2 are more vulnerable to H2O2-induced cell death compared to non-transfected cells [119]. Additionally, TRPM2 expressed in immune cells, such as microglia and macrophages, is able to intensify peripheral and spinal pro-nociceptive inflammatory
Heart and vascular diseases
Aside from the actions in the nervous system, these channels also participation in pathologies affecting the cardiovascular system. The oxidative stress modulation of TRPM2 has implications in endothelial barrier dysfunction. H2O2 exposure promotes an increase in endothelial permeability via a TRPM2-dependent Ca2 + influx [132]. Alterations in the transendothelial resistance (TER) induced by H2O2 decrease by ~ 50% when the TRPM2 activity is suppressed [132], suggesting that at least half of the H2
Cancer
TRPM2 mRNA levels are upregulated in melanomas in which the increased activity is coupled with the methylation of the CpG island [139]. Furthermore, TRPM2 silencing abolishes the proliferation of prostate cancer cells without affecting healthy cells [140]. This finding indicates that regulating the increment in TRPM2 activity in melanoma cells is a plausible therapeutic strategy against cancer progression.
A connection between cancer and TRPM4 has been reported [141]. TRPM4 mRNA expression is
Diabetes, metabolic disorders and bone disease
To study the role played by TRPM2 in pancreatic β-cell physiology, experiments in TRPM2-KO mice were performed [40]. In these mice, renal clearance of glucose was impaired. Additionally, insulin level in the bloodstream was reduced in the TRPM2-KO mice [40], suggesting that inhibiting TRPM2 activity generates and potentiates the loss of glycemic control. TRPM2 has been connected to the insulin secretion of pancreatic β-cells [38], [39], [40], [146] and the downregulation of TRPM2 expression in
Concluding remarks
Although ion channel function is essential for organism viability, changes in or the absence of those functions are decisive in the initiation and progression of several human pathologies, known as channelopathies. Channelopathies most likely explain why ion channels are well-known targets of ancient and modern pharmacology. Most drugs actually in use are based on blocking or activating ion channels. Thus, it is not surprising that ion channels are a popular topic in clinical research.
ROS cause
Conflict of interest
None declared.
Acknowledgments
This work was supported by research grants from Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) 1121078, 1120240 and 1120380 and Millennium Institute on Immunology and Immunotherapy P09-016-F.
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