**1. Introduction**

Reactive oxygen species (ROS) are oxygen-derived molecules with high reactivity that are generated in diverse pathways, including by proteins of the mitochondrial respiratory chain, NADPH oxidase (NOX), dual oxidase (Duox) and cyclooxygenase (COX). Although ROS have been considered as deleterious by-products, they are generated in response to many physiological stimuli such as cytokines, hormones and mechanical force to act as signaling molecules in parallel with reactive nitrogen species (RNS), including nitrogen oxide (NO) [1]. These cellular "redox" signals are considered to play important roles in a wide range of physiological phenomena [1–3]. In the immune system in particular, H2 O2 produced by NOX is important for removal of microorganisms and defects in redox signaling are associated with persistent infections [4]. In contrast, unregulated ROS production in pathological conditions leads to chronic inflammation and tissue damage.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The transient receptor potential (TRP) family is a superfamily of nonselective cation channels that are homologous to the founding TRP member in *Drosophila melanogaster* that is essential for phototransduction [5]. The mammalian TRP superfamily now includes 28 members that can be grouped into six subfamilies based on amino acid sequence similarity: canonical (C), ankyrin (A), vanilloid (V), melastatin (M), polycystin (P), and mucolipin (ML). TRP channels have six transmembrane domains (S1–S6), a pore region between S5 and S6 and cytoplasmic Nand C-termini [6]. The functional TRP channel is a tetramer [7]. TRP channels exhibit a remarkable diversity in their activation mechanisms and can be activated by various ligands, both cold and hot temperatures, mechanical stimuli, or in response to signal transduction pathways. Since TRP channels can be activated by a wide range of environmental stimuli, they are considered to act as cellular "sensors." Many TRP channels, including TRPA1 and TRPM2, which are the focus of the present review, show nonselective cation (Na+ , Ca2+, Mg2+, K+ ) permeability [5], and the activation of these channels causes membrane depolarization and, most importantly, elevated intracellular Ca2+ concentrations ([Ca2+] i ) that can convert environmental information to intracellular signals.

TRPA1 is the exclusive member of the TRPA subfamily and was named for its characteristic N-terminal long 18 ankyrin repeat domain (ARD), a motif that is thought to mediate protein–protein interactions [8]. TRPA1 is abundantly expressed in nociceptive primary afferent sensory neurons that detect nociceptive stimuli. TRPA1 is expressed in sensory neurons of dorsal root ganglia (DRG), trigeminal ganglia (TG), and nodose ganglia, as well as many other organs and tissues, including the brain, heart, small intestine, lung, skeletal muscle, and pancreas [9]. Because TRPA1 has broad sensitivity to reactive compounds, it can detect a wide range of hazardous compounds (see below). TRPA1 function is modulated by endogenous intracellular factors such as membrane lipids and Ca2+, which has bimodal effects on TRPA1 function. EF-hand-like domains in the N-terminus between the 11th and 12th ankyrin repeat of TRPA1 are reported to form a Ca2+-binding site responsible for Ca2+-dependent mTRPA1 activation [10, 11]. TRPA1 desensitization can also depend on Ca2+ [12].

TRPM2 is a member of the TRPM subfamily that functions as a nonselective cation channel. TRPM2 is known as a "channezyme," that is, an ion channel that possesses an enzymatic region, based on its C-terminal Nudix domain that is homologous to the NUDT9 adenosine diphosphoribose (ADPR) pyrophosphatase, an enzyme that converts ADPR to adenosine monophosphate and ribose 5-phosphate [13]. However, the TRPM2 Nudix domain lacks ADPR hydrolase activity and its binding to ADPR is sufficient for channel gating [14, 15]. Adenosine diphosphoribose (ADPR), cyclic ADPR and pyridine dinucleotides, including nicotinamide-adenine-dinucleotide (NAD), nicotinic acid-adenine dinucleotide (NAAD) and NAAD-2′-phosphate (NAADP), have been reported as endogenous agonists for TRPM2. However, TRPM2 activation by pyridine dinucleotides was later shown to have been caused by ADPR contamination, and thereby, pyridine dinucleotides are likely not TRPM2 agonists [16]. TRPM2 is also activated by reactive oxygen species [17] and is therefore considered to be redox-sensitive. TRPM2 is regarded as a "metabolic sensor" because its activity is regulated by cellular and systemic metabolic states such as redox signaling, glucose levels and body temperature [18–20]. As with TRPA1, Ca2+ plays crucial roles in TRPM2 activation [21], and Ca2+ binding to the intracellular pore cavity is necessary for channel activation [22]. Meanwhile, intracellular H+ ions reportedly inhibit TRPM2 function [23].

The transient receptor potential (TRP) family is a superfamily of nonselective cation channels that are homologous to the founding TRP member in *Drosophila melanogaster* that is essential for phototransduction [5]. The mammalian TRP superfamily now includes 28 members that can be grouped into six subfamilies based on amino acid sequence similarity: canonical (C), ankyrin (A), vanilloid (V), melastatin (M), polycystin (P), and mucolipin (ML). TRP channels have six transmembrane domains (S1–S6), a pore region between S5 and S6 and cytoplasmic Nand C-termini [6]. The functional TRP channel is a tetramer [7]. TRP channels exhibit a remarkable diversity in their activation mechanisms and can be activated by various ligands, both cold and hot temperatures, mechanical stimuli, or in response to signal transduction pathways. Since TRP channels can be activated by a wide range of environmental stimuli, they are considered to act as cellular "sensors." Many TRP channels, including TRPA1 and TRPM2, which are

and the activation of these channels causes membrane depolarization and, most importantly,

TRPA1 is the exclusive member of the TRPA subfamily and was named for its characteristic N-terminal long 18 ankyrin repeat domain (ARD), a motif that is thought to mediate protein–protein interactions [8]. TRPA1 is abundantly expressed in nociceptive primary afferent sensory neurons that detect nociceptive stimuli. TRPA1 is expressed in sensory neurons of dorsal root ganglia (DRG), trigeminal ganglia (TG), and nodose ganglia, as well as many other organs and tissues, including the brain, heart, small intestine, lung, skeletal muscle, and pancreas [9]. Because TRPA1 has broad sensitivity to reactive compounds, it can detect a wide range of hazardous compounds (see below). TRPA1 function is modulated by endogenous intracellular factors such as membrane lipids and Ca2+, which has bimodal effects on TRPA1 function. EF-hand-like domains in the N-terminus between the 11th and 12th ankyrin repeat of TRPA1 are reported to form a Ca2+-binding site responsible for Ca2+-dependent mTRPA1

TRPM2 is a member of the TRPM subfamily that functions as a nonselective cation channel. TRPM2 is known as a "channezyme," that is, an ion channel that possesses an enzymatic region, based on its C-terminal Nudix domain that is homologous to the NUDT9 adenosine diphosphoribose (ADPR) pyrophosphatase, an enzyme that converts ADPR to adenosine monophosphate and ribose 5-phosphate [13]. However, the TRPM2 Nudix domain lacks ADPR hydrolase activity and its binding to ADPR is sufficient for channel gating [14, 15]. Adenosine diphosphoribose (ADPR), cyclic ADPR and pyridine dinucleotides, including nicotinamide-adenine-dinucleotide (NAD), nicotinic acid-adenine dinucleotide (NAAD) and NAAD-2′-phosphate (NAADP), have been reported as endogenous agonists for TRPM2. However, TRPM2 activation by pyridine dinucleotides was later shown to have been caused by ADPR contamination, and thereby, pyridine dinucleotides are likely not TRPM2 agonists [16]. TRPM2 is also activated by reactive oxygen species [17] and is therefore considered to be redox-sensitive. TRPM2 is regarded as a "metabolic sensor" because its activity is regulated by cellular and systemic metabolic states such as redox signaling, glucose levels and body temperature [18–20]. As with TRPA1, Ca2+ plays crucial roles in TRPM2 activation

i

, Ca2+, Mg2+, K+

) that can convert environmental information

) permeability [5],

the focus of the present review, show nonselective cation (Na+

activation [10, 11]. TRPA1 desensitization can also depend on Ca2+ [12].

elevated intracellular Ca2+ concentrations ([Ca2+]

to intracellular signals.

204 Redox - Principles and Advanced Applications

TRPM2 is expressed in the plasma membrane of many cell types such as neurons and microglial cells in the brain, vascular endothelial cells, pancreatic β-cells and immunocytes, as well as tissues in the spleen and liver [24]. Several reports showed that TRPM2 also functions in the lysosomal membrane [25, 26].

Despite fluctuating environmental temperatures, endothermic species such as mammals and birds can maintain a constant body temperature through the activity of peripheral thermal sensors in sensory and autonomic neurons and by thermosensitive structures within the preoptic area (POA), anterior hypothalamus, brain stem, spinal cord and possibly other places that regulate body temperatures through autonomic and behavioral mechanisms [27]. TRPM2 was recently shown to be expressed in warmth-sensitive neurons of the POA and in peripheral sensory and autonomic neurons, suggesting that TRPM2 is involved in regulating body temperature [28, 29].
