**5. Pathological and physiological relevance of redox signal-regulated TRPM2 activation**

that human TRPA1 and monkey TRPA1 are not activated by cold stimulus whereas rat TRPA1 and mouse TRPA1 are. Mutation of Gly878 in S5 of rat TRPA1 to Val that is present in human TRPA1 abolished cold sensitivity. A proline hydroxylation-deficient mutant of human TRPA1 (Pro394Ala) was activated by cold stimulation in the presence of low concentrations of H2

(0.1 μM), but wild-type TRPA1 showed no activation [50]. PHD inhibitors could result in activation of wild-type TRPA1 by cold temperature, which is attenuated by mitochondrial ROS

wild type, and a PHD inhibitor increased the response of wild-type TRPA1. In contrast, mouse wild-type TRPA1 was activated by cold temperature and effects of the PHD inhibitor and ROS scavengers were also observed in a mouse TRPA1 clone, confirming that the inhibitory effect of proline hydroxylation was conserved between human and mouse. Several chemotherapeutic agents can cause cold allodynia [51–53]. For instance, the drug oxaliplatin potentiates H2

TRPA1 is also reported to play a physiological role in artery vasodilation, although its activity varies among different types of vascular beds. In cerebral arteries, TRPA1 expressed in the endothelium mediates "endothelium-dependent" vasodilation. ROS such as superoxide anions

cerebral microcirculation [54]. TRPA1 mRNA expression was observed in the endothelium of cerebral arteries, but not in peripheral vascular beds in renal, coronary and mesenteric arteries [55]. TRPA1 protein in the endothelium of cerebral arteries preferentially colocalizes with NOX2, a ROS-generating enzyme, in fenestration of internal elastic lamina where plasma membranes of endothelium and smooth muscle cell are in close contact. ROS generated by NADPH-induced NOX activity led to cerebral artery vasodilation following TRPA1 activation. This vasodilation could be abolished in a variety of ways, including by a NOX inhibitor,

of the intermediate conductance Ca2+-sensitive K channel (IK). Moreover, vasodilation could be mimicked by application of 4-hydroxy-nonenal (4-HNE), a product of lipid peroxidation. These results suggest that ROS-derived lipid peroxidation products activate TRPA1, leading to cytosolic Ca2+ elevation, which in turn activates intermediate conductance Ca2+-sensitive K channels (IK) and membrane hyperpolarization in the endothelium. This change in membrane potential is propagated through gap junctions to smooth muscle cells to promote additional vasodilation. On the other hand, in peripheral arteries, TRPA1 expressed in primary sensory neurons is reportedly involved in "neurogenic" vasodilation. TRPA1 expressed in sensory neurons likely mediates vasodilation in peripheral arteries because TRPA1 is not expressed in the endothelium of peripheral arteries [56]. Topical application of cinnamaldehyde, a TRPA1 agonist, onto mouse ears caused vasodilation in wild-type mice, but not in TRPA1KO mice. TRPA1 agonist-induced vasodilation could be attenuated by a CGRP antagonist, a nonselective NOS or a neuronal NOS (nNOS) inhibitor, suggesting the possible involvement of CGRP and NO release from sensory neurons. In addition, TRPA1 agonist-induced vasodilation is

Taken together, TRPA1 expressed in the endothelium of central arteries is involved in endothelial-dependent vasodilation, whereas TRPA1 expressed in vagal and primary sensory neu-

induced responses in mouse DRG neurons possibly by inhibiting PHD [50].

O2

mediated by formation of superoxide and peroxynitrite.

rons functions in neurogenic vasodilation in peripheral arteries.

O2


) are known to cause vasodilation, leading to increases in

, deferoxamine, which inhibits the Fenton reaction that

), the TRPA1 inhibitor HC-030031 and TRAM34, a blocker

scavenging. H2

(O2 − O2

210 Redox - Principles and Advanced Applications

) and hydrogen peroxide (H2

catalase-mediated degradation of H2

generates hydroxyl radical (OH<sup>−</sup>

O2

O2 - TRPM2 activation induced by H2 O2 promotes cell death due to sustained elevation of intracellular Ca2+ [17] and also increases inflammation and tissue injury [18]. Therefore, numerous reports have shown the implications of TRPM2 activity in oxidative stress-induced cell death of many kinds of tissues and cells [57]. Endogenous and exogenous agents that promote ROS production such as TNFα, β-amyloid, and neurotoxin MPTP also cause neurotoxicity in a TRPM2-dependent manner [17, 58–61]. In addition, ischemia/reperfusion (I/R) injury is a major pathological situation involving unregulated ROS production in stroke, brain trauma, cardiac arrest and other disorders and diseases. Ischemia is the restriction of blood flow that diminishes oxygen (hypoxia/anoxia) and glucose supplies to tissues. When blood supply is restored to the affected tissues, secondary effects associated with I/R injury can occur wherein inflammatory agents and ROS that can cause tissue damage are produced. ROS-evoked TRPM2 activity was reported to aggravate tissue damage in the presence of I/R injury [62–64], and this situation can be explained in part by increased neutrophil migration toward affected tissues [63, 65].

On the other hand, more recent reports suggest that TRPM2 could exert protective roles in I/R injury. One group reported that TRPM2 channels are expressed in the sarcolemma and transverse tubules of adult cardiac myocytes [66, 67]. They also showed that TRPM2KO heart is vulnerable to I/R injury and I/R-induced prolongation of action potential duration was enhanced in TRPM2KO myocytes compared with wild type [67]. Proteomic analysis of I/Raffected ventricles from wild-type and TRPM2KO mice revealed that, relative to wild-type heart, mitochondrial respiratory complex dysfunction in TRPM2KO heart is more severe and is associated with altered expression levels of proteins localized in the mitochondrial inner membrane [68]. Under I/R conditions, TRPM2KO myocyte mitochondria showed lower mitochondrial membrane potential, Ca2+ uniporter activity, ATP levels and oxygen consumption as well as higher ROS levels compared to those seen for wild type. These data suggest that Ca2+ supplied by TRPM2 activity can have a protective role by ameliorating mitochondrial dysfunction and diminishing mitochondrial ROS levels in I/R situations. Similar results were recapitulated in intact and TRPM2-depleted SH-SY5Y neuroblastoma cells treated with the ROS-generating chemotherapeutic agent doxorubicin [69]. Interestingly, these diminished parameters of mitochondrial function in TRPM2KO myocytes were also seen under normoxic conditions [68]. Considering these results, TRPM2 may contribute to the maintenance of basal mitochondrial bioenergetics by supplying Ca2+, which has numerous functions in mitochondrial metabolism [70].

TRPM2 also has roles in inflammation and infection as evidenced by its expression in immunocytes (**Table 1**). In inflammatory situations, ROS are produced and ROS-evoked TRPM2 activity can aggravate inflammation. At sites of inflammation, phagocytes such as neutrophils and macrophages digest deleterious agents and increase oxygen consumption that enhances NOX-mediated production of ROS, phagocytized agents can then be cleared by ROS. TRPM2 is widely expressed in leukocytes, including lymphocytes, neutrophils, monocytes/macrophages, dendritic cells, microglia and mast cells [19, 25, 71–75]. TRPM2 activation by ROS is


**Table 1.** Reports showing the implication of TRPM2 in immune reactivities using *in vivo* and *in vitro* models.

reported to worsen inflammation by elevating cytokine release. Indeed, TRPM2 activation in mouse monocytes elevates H2 O2 -induced release of the neutrophil-attracting chemokine macrophage inflammatory protein-2 (CXCL2) through activation of the Ca2+-dependent tyrosine kinase (Pyk2) and nuclear factor κB (NFκB), and this elevation was attenuated in TRPM2KO monocytes [73]. Supporting these *in vitro* experiments, wild-type mice showed elevated CXCL2 levels and neutrophil infiltration in inflamed colon tissues with ulcerative colitis in a dextran sulfate sodium (DSS)-induced experimental colitis model. These conditions are suppressed in TRPM2KO mice, suggesting that TRPM2 activation in monocytes increased chemokine release and neutrophil migration followed by aggravation of inflammation. In our experiments, TRPM2 activity elevated release of the cytokines granulocyte colony stimulating factor (G-CSF), interleukin-1α (IL-1α), and CXCL2 from macrophages [19]. TRPM2-mediated exacerbation of inflammation also explains pathological conditions associated with chronic pain. TRPM2KO mice showed impaired pain responses in inflammatory pain induced by intraplantar injection of formalin or carrageenan in mice, and neuropathic pain models induced by partial sciatic nerve ligation or spinal nerve transaction [76]. TRPM2 activity in macrophages and microglia is suggested to aggravate chronic pain through CXCL2 release and neutrophil infiltration toward inflamed tissues.

Nod-like receptor family pyrin domain containing-3 (NLRP3) inflammasomes are activated by several conditions of cellular stress, including microbial products, particulate substances, elevated plasma glucose levels that accompany metabolic disorders, intracellular [K+ ] reduction and [Ca2+] i increase [77, 78]. NLRP3 inflammasome is a complex of NLRP3, apoptosisassociated speck-like protein (ASC) and caspase-1 to activate caspase-1 that in turn promotes release of pro-inflammatory cytokines, IL-1β and IL-18. TRPM2 is reported to be involved in the inflammasome activation in macrophages/monocytes. Charged liposomes evoke ROS production, caspase-1 activation and IL-1β release from bone-marrow-derived macrophages (BMDM) [79]. Caspase-1 activation and IL-1β release evoked by liposomes are attenuated by TRPM2 deficiency, although mitochondrial ROS production is comparable to that of wild type. Thioredoxin-interacting protein (TXNIP) is known to bind to NLRP3 and participate in ROS-dependent inflammasome activation [80]. TXNIP expression is up-regulated by high glucose and is involved in ROS production induced by high glucose [81]. Treatment of U937 monocytes with high levels of glucose induced TRPM2 up-regulation, ROS production, caspase-1 activation and IL-1β release, which can be attenuated by TRPM2-siRNA or TRPM2 inhibitors [82]. TXNIP up-regulation by high glucose is also inhibited by TRPM2-siRNA. Upon activation of NOX, p47phox, a cytosolic subunit of NOX, translocates to the plasma membrane. Under high glucose conditions, p47phox translocation is increased as is its colocalization with TRPM2. In addition, co-localization of TXNIP and NLRP3 is enhanced by high glucose conditions, which could also be suppressed by TRPM2-siRNA. These data suggest that Ca2+ influx through TRPM2 can contribute to high glucose-induced ROS production as well as inflammasome activation and amplification of TRPM2 activation to further exacerbate oxidative stress in diseases such as type 2 diabetes.

An important role of macrophages, phagocytosis, is regulated by TRPM2 activity. As mentioned above, macrophages phagocytose deleterious agents such as exogenous pathogens and digest them in phagosomes by producing ROS levels that are toxic to the pathogens. This phagocytosis function is known to be enhanced by temperatures that are associated with fever [83]. Phagocytosis induced by toll-like receptor 2 agonist was enhanced by temperature elevation to febrile range in wild-type macrophages which can detect slight temperature change through TRPM2 activity in the presence of low concentration of ROS [19]. On the other hand, TRPM2KO macrophages showed no such temperature-dependent elevation of phagocytosis, suggesting that ROS generated in phagosomes increases TRPM2 sensitivity to body temperature and that TRPM2 activation by temperature increases phagocytosis. Because TRPM2 is highly localized in phagosomal membranes [84], functional cooperation between TRPM2 and NOX is suggested to increase phagocytosis. As many reports have shown roles for TRPM2 in innate immunity, the physiological roles of TRPM2 have been studied in microbial infection models. In a *Listeria monocytogenes* (Lm) infection model, TRPM2KO mice show lower serum IL-12 and IFNγ levels and a higher mortality rate than wild-type mice; these conditions can be reversed by the application of IFNγ [85]. In contrast to the DSS-induced experimental colitis model [73], Lm-infected TRPM2KO mice have CXCL2 expression and neutrophil infiltration in the spleen that is comparable to wild-type mice. Given that the ratio of activated monocyte (iNOS+ ) is decreased and IL-12 release is unchanged in an *in vitro* cytokine release assay using BMDMs from Lm-infected TRPM2KO, TRPM2 activation is suggested to have important roles in reciprocal activation among macrophages, natural killer cells, and CD8+ T cells mediated by IL-12 and IFNγ during the early phase of Lm infection [86]. TRPM2 deficiency is also

reported to worsen inflammation by elevating cytokine release. Indeed, TRPM2 activation

**Table 1.** Reports showing the implication of TRPM2 in immune reactivities using *in vivo* and *in vitro* models.

macrophage inflammatory protein-2 (CXCL2) through activation of the Ca2+-dependent tyrosine kinase (Pyk2) and nuclear factor κB (NFκB), and this elevation was attenuated in TRPM2KO monocytes [73]. Supporting these *in vitro* experiments, wild-type mice showed elevated CXCL2 levels and neutrophil infiltration in inflamed colon tissues with ulcerative colitis in a dextran sulfate sodium (DSS)-induced experimental colitis model. These conditions are suppressed in TRPM2KO mice, suggesting that TRPM2 activation in monocytes increased chemokine release and neutrophil migration followed by aggravation of inflammation. In our experiments, TRPM2 activity elevated release of the cytokines granulocyte colony stimulating factor (G-CSF), interleukin-1α (IL-1α), and CXCL2 from macrophages [19]. TRPM2-mediated exacerbation of inflammation also explains pathological conditions associated with chronic pain. TRPM2KO mice showed impaired pain responses in inflammatory pain induced by intraplantar injection of formalin or carrageenan in mice, and neuropathic pain models induced by partial sciatic nerve ligation or spinal nerve transaction [76]. TRPM2 activity in macrophages and microglia is suggested to aggravate chronic pain through CXCL2

Nod-like receptor family pyrin domain containing-3 (NLRP3) inflammasomes are activated by several conditions of cellular stress, including microbial products, particulate substances,


monocyte↓

,

O2

*In vivo* **model The effects of TRPM2 down regulation** DSS-induced colitis [73] CXCL2↓, neutrophil infiltration↓

*Listeria monocytogenes* [85] Survival rate↓, CXCL2→,

CLP-induced sepsis [87] Survival rate↓, inflammation↑,

PA i.t., CLP [84] Survival rate↓, bacterial clearance↓

inflammation↓

LPS i.p. [89] Survival rate↓, inflammation↑, CXCL2↑, TNFα↑, IL-6↑, neutrophil

*In vitro* **model Stimulus The effect of TRPM2 down regulation**

Peritoneal macrophage [19] Zymosan CXCL2↓, GCSF↓, IL-1α↓, IL-1β↓#

BMDM [76] Liposome Inflammasome activation↓, IL-1β↓,

U937 monocyte [82] High glucose Inflammasome activation↓,

BMDM [84] PA, SA Phagosomal acidification↓,

neutrophil infiltration→, iNOS+

infiltration↑, ROS production↑

O2 CXCL8 (human homolog of CXCL2)↓

TNFα→, Temp-phagocytosis↓

TNFα→, ROS production→

NOX activation↓, IL-1β↓

Bacterial clearance↓

IL-6↑, HMGB↑, bacterial clearance↓

release and neutrophil infiltration toward inflamed tissues.

in mouse monocytes elevates H2

U937 monocyte [73] H2

212 Redox - Principles and Advanced Applications

reported to increase the mortality rate in a cecal ligation and puncture (CLP)-induced polymicrobial sepsis model [87]. Moreover, TRPM2KO mice show increased bacterial burden and enhanced inflammation and injury in tissues. TRPM2-deficient BMDM show lower bacterial killing than that of wild type without noticeable effects on phagocytosis. Lipopolysaccharide (LPS) treatment of BMDM from wild-type and TRPM2KO mice revealed that heme oxygenase-1 (HO-1) induction observed in wild-type cells did not occur in TRPM2KO cells and the induction in wild-type cells is inhibited by chelating Ca2+, suggesting that [Ca2+]i increases mediated through TRPM2 lead to HO-1 expression. Bacterial killing in phagosomes is also reported to be regulated by TRPM2 activity [84]. TRPM2 deficiency increases the bacterial burden of *Pseudomonas aeruginosa* (PA) and *Staphylococcus aureus* (SA) in BMDM without affecting phagocytosis. TRPM2 functionally expressed in phagosomal membrane promotes acidification of SA-internalized phagosomes that is a hallmark of phagosomal maturation and is regarded to be crucial for degradation of phagocytosed particles and up-regulation of bacterial killing [88].

Contrary to reports showing that TRPM2 up-regulates inflammation/innate immunity, protective anti-inflammatory roles of TRPM2 were also reported in a LPS-induced lung inflammatory model [89]. After intraperitoneal injection with LPS, TRPM2KO mice had higher mortality with pronounced lung edema than did wild-type mice. Histopathology of tissues from TRPM2KO mice showed increased levels of tissue cytokines including CXCL2, TNFα, IL-6 and myeloperoxidase (MPO) activity, suggesting enhanced neutrophil infiltration in mice lacking TRPM2. ROS release and oxidative DNA damage in TRPM2KO cells are significantly larger than those in wild-type cells, and a TRPM2 inhibitor increased ROS release from wild-type cells that was equivalent to that of TRPM2KO, thus indicating the inhibitory effects of TRPM2 activity. As activity of the electrogenic NOX enzyme is known to be voltage-sensitive [90], membrane depolarization through TRPM2 is suggested to negatively regulate NOX activity, and the absence of this regulatory mechanism in TRPM2KO mice could enhance ROS production and aggravate inflammation. Nonetheless, the role of TRPM2 in immunity remains controversial, and its activation could depend on the stimulus type, particularly since immunogens can activate multiple cascades (**Table 1**). In addition, immune reactivity is strongly related to body temperature [83, 91]. Thus, the temperature dependence of TRPM2 must be considered [19]. Outcomes could also be affected depending on the extent of TRPM2 activity, e.g., Ca2+ influx through TRPM2 could be beneficial for many Ca2+-dependent events, whereas large Ca2+ influx could cause Ca2+ overload.

TRPM2 is also known to contribute to the regulation of blood glucose levels (**Figure 4**) likely because of its functional expression in pancreatic β-cells [92], which secrete insulin in response to elevated blood glucose. Although the primary pathway of glucose-stimulated insulin secretion is through ATP-sensitive K+ (KATP) channel closure and L-type voltage-gated Ca2+ channel activation to increase [Ca2+] i , many other ion channels, including TRPM2, are reported to be involved in [Ca2+] i -increases to evoke insulin secretion [93]. ROS are produced in response to extracellular signals such as insulin, cytokines, hormones and blood glucose elevation in pancreatic β-cells [94, 95]. In addition, expression of the antioxidant enzyme catalase and glutathione reductase in the pancreas is very low [96], indicating that the intracellular redox state of β-cells could be affected at a physiological level by the systemic metabolic state. Intracellular Ca2+-oscillations evoked by high glucose concentrations are attenuated in TRPM2KO pancreatic β-cells [97]. In

reported to increase the mortality rate in a cecal ligation and puncture (CLP)-induced polymicrobial sepsis model [87]. Moreover, TRPM2KO mice show increased bacterial burden and enhanced inflammation and injury in tissues. TRPM2-deficient BMDM show lower bacterial killing than that of wild type without noticeable effects on phagocytosis. Lipopolysaccharide (LPS) treatment of BMDM from wild-type and TRPM2KO mice revealed that heme oxygenase-1 (HO-1) induction observed in wild-type cells did not occur in TRPM2KO cells and the

mediated through TRPM2 lead to HO-1 expression. Bacterial killing in phagosomes is also reported to be regulated by TRPM2 activity [84]. TRPM2 deficiency increases the bacterial burden of *Pseudomonas aeruginosa* (PA) and *Staphylococcus aureus* (SA) in BMDM without affecting phagocytosis. TRPM2 functionally expressed in phagosomal membrane promotes acidification of SA-internalized phagosomes that is a hallmark of phagosomal maturation and is regarded to be crucial for degradation of phagocytosed particles and up-regulation of

Contrary to reports showing that TRPM2 up-regulates inflammation/innate immunity, protective anti-inflammatory roles of TRPM2 were also reported in a LPS-induced lung inflammatory model [89]. After intraperitoneal injection with LPS, TRPM2KO mice had higher mortality with pronounced lung edema than did wild-type mice. Histopathology of tissues from TRPM2KO mice showed increased levels of tissue cytokines including CXCL2, TNFα, IL-6 and myeloperoxidase (MPO) activity, suggesting enhanced neutrophil infiltration in mice lacking TRPM2. ROS release and oxidative DNA damage in TRPM2KO cells are significantly larger than those in wild-type cells, and a TRPM2 inhibitor increased ROS release from wild-type cells that was equivalent to that of TRPM2KO, thus indicating the inhibitory effects of TRPM2 activity. As activity of the electrogenic NOX enzyme is known to be voltage-sensitive [90], membrane depolarization through TRPM2 is suggested to negatively regulate NOX activity, and the absence of this regulatory mechanism in TRPM2KO mice could enhance ROS production and aggravate inflammation. Nonetheless, the role of TRPM2 in immunity remains controversial, and its activation could depend on the stimulus type, particularly since immunogens can activate multiple cascades (**Table 1**). In addition, immune reactivity is strongly related to body temperature [83, 91]. Thus, the temperature dependence of TRPM2 must be considered [19]. Outcomes could also be affected depending on the extent of TRPM2 activity, e.g., Ca2+ influx through TRPM2 could be beneficial for many Ca2+-dependent events,

TRPM2 is also known to contribute to the regulation of blood glucose levels (**Figure 4**) likely because of its functional expression in pancreatic β-cells [92], which secrete insulin in response to elevated blood glucose. Although the primary pathway of glucose-stimulated insulin secretion

signals such as insulin, cytokines, hormones and blood glucose elevation in pancreatic β-cells [94, 95]. In addition, expression of the antioxidant enzyme catalase and glutathione reductase in the pancreas is very low [96], indicating that the intracellular redox state of β-cells could be affected at a physiological level by the systemic metabolic state. Intracellular Ca2+-oscillations evoked by high glucose concentrations are attenuated in TRPM2KO pancreatic β-cells [97]. In

(KATP) channel closure and L-type voltage-gated Ca2+ channel activa-

, many other ion channels, including TRPM2, are reported to be involved


increases

induction in wild-type cells is inhibited by chelating Ca2+, suggesting that [Ca2+]i

bacterial killing [88].

214 Redox - Principles and Advanced Applications

whereas large Ca2+ influx could cause Ca2+ overload.

is through ATP-sensitive K+

i

tion to increase [Ca2+]

in [Ca2+] i

**Figure 4.** Functional involvement of TRPM2 in regulating insulin secretion from pancreatic β-cells. GLUT2, glucose transporter 2; KATP, ATP-sensitive K+ channel; VGCC, voltage-gated Ca2+ channel; GHSR, growth hormone secretagogue receptor; α2R, α2 adrenergic receptor; IncretinR, incretin receptor; EPAC, exchange protein directly activated by cAMP; Mito, mitochondria.

addition, heat-evoked responses in Wt b-cells were enhanced by H2 O2 in a dose-dependent manner, however, TRPM2KO cells completely lacked the response [20]. Glucose-stimulated insulin secretion from pancreatic islets was attenuated by TRPM2 deficiency [97], and the N-acetyl cysteine-sensitive fraction of glucose-stimulated insulin secretion was increased by temperature elevation from 33 °C to 40 °C in wild type, but not TRPM2KO cells, suggesting insulin secretion could be up-regulated by ROS and temperature-dependent TRPM2 activity [20]. TRPM2KO mice show blunted insulin secretion and higher blood glucose levels in oral and intraperitoneal glucose tolerance tests relative to wild-type mice, which highlights TRPM2 function in blood glucose regulation *in vivo* [97].

TRPM2 could also be involved in hormone-regulated insulin secretion. Glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are incretin hormones released from the intestine to enhance glucose-stimulated insulin secretion from pancreatic islets [98]. The up-regulation of insulin release by incretin was shown to be TRPM2-dependent [97, 99]. This increase in insulin secretion is mediated by generation of cAMP and activation of exchange protein directly activated by cAMP (EPAC). By inhibiting the same pathway, insulinostatic effects of ghrelin and adrenaline are reportedly achieved [100, 101]. Although the involvement of ROS-evoked TRPM2 activity in such hormone-regulated insulin secretion has not been defined, TRPM2 participation in glucose metabolism seems likely. In contrast, TRPM2 mediated aggravation of inflammation was reported to cause insulin resistance in peripheral tissues [102]. High-fat diet (HFD)-induced obesity, chronic inflammation and insulin resistance with elevated plasma and tissue cytokines are also reported to be related [103]. TRPM2KO mice show resistance to HFD-induced obesity, as well as lower cytokine levels and macrophage infiltration in adipose tissue compared with wild-type mice [102]. Energy expenditure and glucose uptake to muscle and heart are higher in TRPM2KO mice than in wildtype animals, and this increase is accompanied by elevated expression levels of metabolic and mitochondrial genes. These data suggest that, in addition to regulating insulin secretion, TRPM2 could control glucose metabolism in glucose-consuming tissues.
