Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Transient Receptor Potential Cation Channel Subfamily M Member 2

  • Lin-Hua Jiang
  • Sharifah Alawieyah Syed Mortadza
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101875


Historical Background

Transient receptor potential (TRP) cation channel subfamily M member 2 (TRPM2) was identified in the search for mammalian genes encoding homologues of the transient receptor potential (Trp) proteins that forms Ca2+-permeable cationic channels required for photo-transduction in Drosophila melanogaster fruit fly (Hardie and Minke 1992). It was firstly named the seventh classical TRP protein (TRPC7) that exhibits sequence relatedness with Drosophila Trp proteins (Nagamine et al. 1998) and subsequently renamed LTRPC2, the second member of the long TRP channel protein family characterized with exceptionally long N- and C-termini (Harteneck et al. 2000). In the efforts devoted to unifying the terminology, the mammalian TRP proteins, 28 in total, are divided, based on amino acid sequence similarity, into six subfamilies: classical (TRPC), vanilloid (TRPV), melastatin (TRPM), ankyrin (TRPA), polycystin (TRPP), and mucolipin (TRPML) (Montell et al. 2002; Clapham 2003). As a result, LTRPC2 was changed to its current name, TRPM2, to indicate that it is the second member of the TRPM subfamily.

Tissue and Cell Distribution

The genes for human, rat, and mouse TRPM2 proteins are molecularly cloned. The human TRPM2 gene is located on the chromosome 21q22.3 that spans approximately 90 kb, contains 32 exons, and encodes a protein of 1503 amino acid residues with a molecular weight of about 171 kDa (Nagamine et al. 1998). In addition to the full-length protein, several short alternative splicing variants of human TRPM2 proteins are reported (Jiang et al. 2010). The full-length rat and mouse TRPM2 proteins are 1507 amino acid residues in length (Jiang et al. 2010). The TRPM2 protein orthologue from sea anemone Nematostella vectensis has been recently studied; this protein consists of 1553 amino acid residues and exhibits 31% sequence identity with human TRPM2 protein (Kuhn et al. 2015).

TRPM2 expression has been documented at mRNA, protein, and/or functional levels in many tissues including the brain, heart, kidney, liver, and pancreas and in diverse cell types, such as neurons in both central nervous system (CNS) (e.g., hippocampal, striatal, cortical, and hypothalamic neurons) and peripheral nervous system (PNS) (e.g., dorsal root ganglion neurons), cardiomyocytes, and all types of immune cells including microglia cells, endothelial cells, epithelial cells, hepatocytes, and pancreatic β-cells. The TRPM2 channel is localized on the cell surface in aforementioned cell types, except dendritic cells and pancreatic β-cells. In dendritic cells, the TRPM2 channel is exclusively present in the lysosome, and in pancreatic β-cells, it exists in both plasma and lysosomal membranes (Jiang et al. 2010).

Structural Characteristics

All TRP proteins including TRPM2 have a common membrane topology that comprises intracellular N- and C-termini, six alpha-helical transmembrane segments (S1–S6), and a reentrant loop between the S5 and S6 (Fig. 1). Four TRPM2 proteins or subunits interact to assemble a homo-tetrameric complex, with a central aqueous pore as the ion permeation pathway formed by the S5, S6, and the loop between them (termed pore-forming loop or P-loop) from each subunit (Fig. 1). While the TRPM2 channel structure is still not available, the electron cryo-microscopic structures of TRPV1 channel have confirmed these conserved structural characteristics (Liao et al. 2013). Site-directed mutagenesis studies have been identified highly conserved in the P-loop; Asp987 in the human TRPM2 channel is critical in determining Ca2+ permeability of the TRPM2 channel (Xia et al. 2008). A naturally occurring mutation in the P-loop, P1018L, which is found in a subset of Guamanian patients with amyotrophic lateral sclerosis and parkinsonism-dementia, confers rapid channel inactivation (Hermosura et al. 2008).
Transient Receptor Potential Cation Channel Subfamily M Member 2, Fig. 1

Structural characteristics, subcellular localization, and activation of TRPM2 channels. TRPM2 channels are a tetrameric complex, with each subunit composed of intracellular N- and C-termini, six transmembrane segments (S1–S6), and a pore-forming (P) loop between the S5 and S6. Asp876 in the ion selectivity filter of the P-loop is critical in determining Ca2+ permeability of the TRPM2 channel. A natural mutation of Pro1017 to Leu in the P-loop confers rapid channel inactivation. The N-terminus contains four MHD domains, and an IQ-like motif mediating a calmodulin-dependent interaction with intracellular Ca2+ and thereby conferring Ca2+-induced channel activation or facilitation of channel activation. The TRPM2 channels are located on the cell surface in a majority of cells mediating Ca2+ influx but as lysosomal Ca2+ release channel in dendritic cells. The C-terminus comprises a CC domain responsible for channel assembly and a NDUT9-H domain underpinning specific activation of the TRPM2 channel by intracellular ADPR. ROS activate the TRPM2 channel, mainly through the mechanisms engaging PARP-1/PARG in the nucleus or NADase in the mitochondria to generate ADPR from NAD. The TRPM2 channels are also sensitive to activation by warm temperature, although the mechanism is not fully understood. Activation of the TRPM2 channel leads to an increase in the cytosolic Ca2+ concentration, which triggers diverse intracellular signaling pathways. Abbreviations: MHD TRPM homology domain; CC coiled-coil; NUDT9-H, NUDT9 homology domain; ROS, reactive oxygen species; NAD, nicotinamide adenine dinucleotide; ADPR, ADP-ribose; PARP, poly(ADPR) polymerase; PARG, poly(ADPR) glycohydrolase; pADPR, poly(ADPR) moiety

The N-terminus of TRPM2 proteins contains four stretches of amino acid residues that are relatively conserved within the TRPM subfamily, termed the TRPM homology domains (MHD) I–IV. These domains have not been assigned with specific channel function. Nonetheless, an IQ-like calmodulin (CaM)-binding motif, located within the MHD III, has been shown to mediate CaM-dependent interaction of the TRPM2 channel with Ca2+, thereby conferring Ca2+-induced channel activation or facilitation of channel activation by other agonists (Du et al. 2009). The proximal C-terminal region of TRPM2 proteins has a coiled-coil (CC) domain, which is highly conserved in the TRPM subfamily and participates in subunit tetramerization or channel formation (Mei et al. 2006). The distal C-terminal region of TRPM2 proteins exhibits substantial sequence homology to NUDT9, an enzyme hydrolyzing ADP-ribose (APDR) into AMP and ribose phosphate. This unique NUDT9-H domain led to identification of ADPR as an intracellular signaling molecule that specifically gates the TRPM2 channel (Perraud et al. 2001). An early study showed that the NUDT9-H domain, when expressed on its own, exhibited low but detectable ADPR hydrolase activity (Perraud et al. 2001), which is however refuted in a recent study (Iordanov et al. 2016).


ADPR activates the TRPM2 channels with an EC50 (the concentration evoking 50% of the maximal response) of 10∼90 μM, depending on the cell types and the methods used to measure the channel activity (Jiang et al. 2010). Several structure or metabolism-related ADPR homologues, including cyclic ADP (cADPR), nicotinamide adenine dinucleotide (NAD), nicotinic acid adenine dinucleotide (NAAD), and NAAD-2′-phosphate (NAADP), have been shown to activate the TRPM2 channels in submillimolar to millimolar concentrations (Jiang et al. 2010). However, there is evidence that argues against the notion that these chemicals gate the TRPM2 channels as ADPR (Toth and Csanady, 2010). As mentioned above, cytosolic Ca2+ can activate the TRPM2 channels via the above-mentioned IQ-like CaM-binding motif in the N-terminus (Du et al. 2009). Two recent studies show that warm temperature activates the TRPM2 channels in a subset of sensory neurons in the PNS (Tan and McNaughton, 2016) and hypothalamic neurons in the brain (Song et al. 2016). Finally, the TRPM2 channels are potently activated in response to reactive oxygen species (ROS) and reactive nitrogen species (RNS), which mainly promote ADPR generation via mechanisms engaging poly(ADPR) polymerases (PARP), particularly PARP-1 in the nucleus, or NADase in the mitochondria (Jiang et al. 2010) (Fig. 1). There is also evidence to support that ROS reduces the temperature threshold for TRPM2 channel activation via oxidizing Met214 in the N-terminus (Kashio et al. 2012).

Several structurally distinctive chemicals were reported to inhibit the TRPM2 channels with IC50 values (the concentration inhibiting 50% of agonist-induced responses) in a micromolar range. These include flufenamic acid (FFA), a nonsteroidal anti-inflammatory metabolite; clotrimazole and econazole, imidazole antifungal agents; N-(p-amylcinnamoyl) anthranilic acid (ACA); and 2-aminoethoxydiphenyl borate (2-APB) (Jiang et al. 2010). A more recent study shows that curcumin, a natural plant-derived polyphenol in turmeric spice, inhibits the TRPM2 channel activation with an IC50 of approximately 50 nM (Kheradpezhouh et al. 2016). The mechanisms of action for these inhibitors are not well understood, although it is thought that they inhibit the TRPM2 channel activation or block the open channel. It is worth pointing out that none of these inhibitors are TRPM2 channel specific. A recent study has reported that 8-phenyl-2′-deoxy-ADPR is a potent antagonist with an IC50 of 3 μM at the human TRPM2 channel (Moreau et al. 2013). PARP inhibitors, such as PJ34, DPQ, and 2AB, are commonly used to inhibit ROS-induced TRPM2 channel activation.

Physiological Functions

The efforts in elucidating the physiological functions of TRPM2 channels were largely hampered by the lack of TRPM2 channel-specific inhibitors. Recent in vivo and in vitro studies using transgenic TRPM2 knockout mice and derived cells have unraveled an important role of the TRPM2 channel in a number of physiological functions, including glucose-induced insulin secretion from pancreatic β-cells (Uchida et al. 2011), thermoregulation (Song et al. 2016), protection against cardiac damage by ischemia-reperfusion or hypoxia-reoxygenation (Hoffman et al. 2015), defense against endotoxin-induced lung inflammation (Di et al. 2012) and polymicrobial sepsis (Qian et al. 2014), and innate and adaptive immune responses (Knowles et al. 2011), particularly generation of proinflammatory cytokines such as interleukin-1β and tumor necrosis factor-α from immune cells in response to exposure to pathogen or danger-associated molecule patterns (Wehrhahn et al. 2010; Kashio et al. 2012; Zhong et al. 2013).

Role in Diseases

Oxidative stress or excessive ROS is long recognized to be detrimental to cells. It was demonstrated shortly after recognition of the TRPM2 channels as ADPR-gated cationic channels that TRPM2 channel activation acts as an important mechanism underlying ROS-induced cell death (Hara et al. 2002). ROS-induced cell death represents the most common role of the TRPM2 channels established in diverse cell types, including neurons (Ye et al. 2014), cardiomyocytes (Yang et al. 2006), pancreatic β-cells (Manna et al. 2015), and macrophage cells (Zou et al. 2013). Further studies, using the TRPM2 knockout mice in combination of disease models, have disclosed a critical role for ROS-induced TRPM2 channel-mediated cell death in a diversity of pathological or disease conditions, ranging from ischemic kidney injury (Gao et al. 2014), paracetamol overdosing-induced liver damage (Kheradpezhouh et al. 2014), diabetes (Manna et al. 2015) to ischemia brain damage (Alim et al. 2013; Nakayama et al. 2013; Shimizu et al. 2013; Ye et al. 2014; Gelderblom et al. 2014). In addition, studies using pharmacological and genetic interventions including using TRPM2 knockout mice have revealed a crucial role for the TRPM2 channels in ROS-induced endothelial barrier dysfunction (Hecquet et al. 2008), colitis (Yamamoto et al. 2008), development of diet-induced obesity and insulin resistance (Zhang et al. 2012), inflammatory pain (Haraguchi et al. 2012), and Alzheimer’s diseases (Park et al. 2014; Ostapchenko et al. 2015).


The human TRPM2 protein was identified in 1998 as one of the mammalian homologues of Drosophila Trp channel proteins. As briefly described above, the TRPM2 proteins show wide tissue and cell expression and forms Ca2+-permeable cationic channels gated by intracellular ADPR. The TRPM2 channels are also activated by warm temperature, intracellular Ca2+, and ROS. Studies over the past nearly 20 years, particularly those using TRPM2 knockout mice that became available from 2008, provide convincing experimental evidence to show that the TRPM2 channels serve as a sensor for warm temperature or oxidative stress and play an important role in a variety of physiological functions and pathological conditions. Considering the momentous advancement and increasing availability of cryo-EM and other imaging techniques, let us hope that the atomic structures of the TRPM2 channels become available in the coming years. Such structural information will provide better insights into ligand binding, channel gating, and ion permeation and, importantly, will revolutionize the approaches of screening and design of specific and potent TRPM2 channel inhibitors, to be used as research tools to better understand the role of human TRPM2 channels in health and disease and hopefully in the foreseeable future as therapeutics to treat ROS-related diseases.



SSM is a recipient of Malaysian governmental scholarship. The researches in LHJ's lab described here have been supported by Wellcome Trust, Alzheimer’s Research Trust, Nature Science Foundation of China, Department of Education Henan Province, and Xinxiang Medical University. We apologize that we have not cited the literature in full due to space limitation.


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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Lin-Hua Jiang
    • 1
    • 2
  • Sharifah Alawieyah Syed Mortadza
    • 1
  1. 1.School of Biomedical SciencesUniversity of LeedsLeedsUK
  2. 2.Department of Physiology and Neurobiology, and Sino-UK Joint Laboratory of Brain Function and InjuryXinxiang Medical UniversityXinxiangChina