TRPM4 in Disease: History
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Contributor:
Norbert Szentandrássy
,
Sarmoko Sarmoko

Transient receptor potential melastatin 4 (TRPM4) is a unique member of the TRPM protein family and, similarly to TRPM5, is Ca2+ sensitive and permeable for monovalent but not divalent cations. It is widely expressed in many organs and is involved in several functions; it regulates membrane potential and Ca2+ homeostasis in both excitable and non-excitable cells. 

  • TRPM4
  • Skeletal
  • Urinary Bladder
  • Cancer
  • CNS
  • heart

1. TRPM4 in Skeletal Muscle

The role of TRPM4 is not widely known in skeletal muscle as only a few reports mention TRPM4 in relation to skeletal muscle, regardless of the fact that its presence was described in both murine [1][2] and human skeletal muscle tissue [3]. In the murine animal model of Duchenne muscular dystrophy, the TRPM4 mRNA level was much smaller in skeletal muscles of both 30 and 100 (but not 365)-day-old animals compared with those of healthy animals. This reduced TRPM4 expression could be only a secondary effect in response to the increased Ca2+ influx in dystrophy muscles [2]. Despite this, the contribution of TRPM4 to store operated Ca2+ entry and stretch-activated or background Ca2+ entry in muscle fibers is missing so far [4]. Moreover, the role of TRPM4 was only suggested as it might regulate membrane potential and, due to that, modulate the driving force for Ca2+ entry [5]. Alterations in TRPM4 splicing were reported in myotonic dystrophy 1 in both embryonic and adult muscle [6].

2. TRPM4 in Urinary Bladder

TRPM4 function in the smooth muscle of the urinary bladder made TRPM4 a potential target of overactive bladders [7]. TRPM4 expression was detected not only in the smooth muscle of the bladder itself [8][9][10] but also on the apical membrane of the umbrella cells of the urothelium [11][12]. In the detrusor muscle of both rats and guinea pigs, 9-phenanthrol dose-dependently inhibited spontaneous, carbachol-, KCl-, and nerve-evoked contractions [8][9][13]. The compound 9-phenanthrol was more effective, compared with glibenclamide, in reducing KCl-induced phasic contractions of the guinea pig detrusor muscle, but the two drugs were equally effective in reducing spontaneous contractions [14]. In case of the murine detrusor muscle, TRPM4 might play a role in setting the resting membrane potential, and, thereby, the basal tone can also influence the cholinergic signaling [15]. The detrusor muscle and mucosal cells increased their TRPM4 expression after spinal cord transection in mice, which led to spontaneous phasic activity [16]. As 9-phenanthrol greatly reduced this phasic activity, a potential role for TRPM4 in detrusor overactivity was suggested. Even more importantly, the human detrusor muscle, which also expressed TRPM4, was more sensitive to a 9-phenanthrol-induced reduction of contractility than the detrusor muscles of rats or guinea pigs [17]. Provence et al. suggested a spatial and functional coupling between TRPM4 channels and IP3 receptors in detrusor smooth muscle cells obtained from healthy humans [10]. Moreover, in guinea pigs, an overall reduction of the TRPM4 protein was reduced during aging and in line with that, the action of 9-phenanthrol (inhibition of the amplitude and muscle force of spontaneous and KCl-induced phasic contractions) was less pronounced in adult animals compared with juvenile ones [18].

3. The Role of TRPM4 in the Endothelium

TRPM4 can be involved in the function of endothelial cells. Ca2+-activated nonselective current was reported in Ea.hy926 cells, an endothelial cell line derived from human umbilical vein [19]. Similarly, a non-selective cation current was recorded in macrovascular endothelial cells derived from human umbilical veins, and the current was inhibited by various types of nitric oxide (NO) donors [20]. The ion channels responsible for the current might influence NO release by regulating the driving force for Ca2+ entry. The endothelial expression of TRPM4 was detected in a rat model of spinal cord injury [21]. In that model, preventing the in vivo expression of TRPM4 eliminated the secondary hemorrhage and greatly reduced lesion volume and, even more importantly, produced a substantial improvement in neurological function. Pharmacological (9-phenanthrol or glibenclamide) siRNA- or TRPM4-dominant negative mutant-mediated inhibition/suppression of TRPM4 protected the endothelium from lipopolysaccharide-induced endothelial cell death in human umbilical vein endothelial cells [22]. Similarly, the inhibition of TRPM4 expression in a rat ischemic stroke model improved the outcome, although this effect was only transient, in correlation with the ischemia-induced transient increase of TRPM4 expression [23]. Reduced TRPM4 expression induced by siRNA treatment led to decreased endothelial protein expression and, at the same time, increased expression of fibrotic and extracellular matrix markers [24]. The mechanism behind this effect was the increase of intracellular Ca2+ levels, the induction of TGF-β1 and TGF-β2 expression, and finally the nuclear translocation of the profibrotic transcription factor SMAD4. In conclusion, appropriate levels of TRPM4 may be beneficial and help to avoid endothelial dysfunction during inflammatory diseases [24]. TRPM4 increased but did not initiate H2O2-induced human umbilical vein endothelial cell depolarization and migration; therefore, it might also be involved in angiogenesis [25]. TRPM4 seems to be involved in endothelial cell functions and might become an important drug target.

4. The Role of TRPM4 in Cancer

TRPM4 was associated with several types of malignant diseases [26]. Usually overexpression of TRPM4 was reported in several types of malignancies, such as prostate cancer [27][28]; breast, cervical, and endometrial cancer [29][30][31][32]; diffuse large B cell lymphoma [33][34]; and acute myeloid leukemia [35]. TRPM4 protein overexpression was observed in colorectal cancer [36], but other studies reported either no differences in TRPM4 expression [37] or lower TRPM4 mRNA levels in colorectal cancer compared with normal tissue [38]. In the case of the urinary bladder, the TRPM4 protein was only detected in urothelium, and its expression was equal in cancer and control groups, which raises questions about its role in that type of malignancy [39]. TRPM4 might be useful as a diagnostic marker in the differentiation of eosinophilic renal tumors [40].
Endometrial carcinoma with reduced TRPM4 mRNA expression significantly correlated with poor prognosis, as well as overall and recurrence-free survival, making TRPM4 a prognostic factor [31][41]. Accordingly, TRPM4 silencing increased the cell viability and migration rate of the AN3CA endometrial cancer cell line [31]. On the contrary, in the cervical-cancer-derived cell line HeLa shRNA-mediated TRPM4 downregulation led to decreased cell proliferation, while overexpression of TRPM4 in a HEK293-derived cell line (T-REx 293) increased cell proliferation via the β-catenin pathway [42].
Two studies reported the involvement of TRPM4 in breast cancer, where its expression was increased on both the mRNA and protein levels [29][30]. Moreover, there was a correlation between increased TRPM4 protein expression and an estrogen response as well as Epithelial Mesenchymal Transmission (EMT) gene sets, resulting in worse clinic-demographical parameters [29]. Interestingly, the K+ channel tetramerization domain 5 protein was identified as a novel TRPM4-interacting protein, which enhances its Ca2+ sensitivity, promotes cell migration and contractility, and can also be used as a prognostic factor [30].
In colorectal cancer, as mentioned before, the expression pattern of TRPM4 is contradictory. The most recent study analyzed samples from 379 patients [36], while the earlier ones used either mRNA samples from 93 patients only [38] or 4 independent cultures of human colorectal (HT29) cell lines [37]. High TRPM4 protein expression in human colorectal tumor buds was associated with an epithelial–mesenchymal transition and infiltrative growth patterns. The highest level of TRPM4 protein expression was found in cells from late-stage metastatic cancer [36]. CRISPR/cas9 TRPM4 KO clones of colorectal carcinoma HCT116 cells showed a tendency toward decreased migration, invasion, cell viability, and proliferation, as well as exhibiting a shift in cell cycle. Stable overexpression of wild-type TRPM4, but not the non-conducting, dominant-negative TRPM4 mutant in CRISPR/cas9 TRPM4 KO clones, rescued the decrease in cell viability and cell cycle shift [36]. The importance of TRPM4 ion conductivity in modulation of viability and cell cycle shift makes TRPM4 a potential target in the treatment of colorectal cancer.
TRPM4 mRNA upregulation (together with the downregulation of other genes) in CD5+ subtypes of diffuse large B-cell lymphoma (DLBCL) patients was associated with a poorer prognosis compared with CD5− patients [34]. The TRPM4 protein was not detected in normal B cells within lymphoid tissues (reactive tonsil, lymph node, and appendix) but was observed in epithelial cells of reactive tonsils, epithelial luminal cells of hyperplastic prostates, endometrial glands, and distal tubules of kidneys [33]. Out of 189 DLBCL cases, 26% exhibited 10–100% TRPM4-positive tumor cells, and the high TRPM4 expression in activated B cell-like DLBCL subtype was associated with a reduced overall and progression-free survival [33]. TRPM4 expression also increased in those acute myeloid leukemia patients and acute myeloid leukemia cell lines where the MLL gene (a methyltransferase for histone H3 lysine 4) was rearranged [35]. TRPM4 KD by siRNA in MLL-rearranged cell lines inhibited proliferation and cell cycle progression through the AKT/GLI1/Cyclin D1 pathways. The transcription factor HOXA9 was found to be responsible for the upregulation of TRPM4 expression by binding to its promoter in MLL rearranged cell lines [35]. The up-regulation of TRPM4, the only surface protein among up-regulated gene products in acute myeloid leukemia cell lines made TRPM4 a potential novel therapeutic target [43].
TRPM4 is well studied in prostate cancer. TRPM4 mRNA was present in normal human [3] and rat prostate tissue [44]. Higher levels of TRPM4 mRNA were found in prostate cancer upon comparing a pool of 11 normal and 13 precancerous or cancerous prostate tissue-derived data using digital libraries [45]. TRPM4 can be a driver gene of androgen-independent prostate cancer in vitro [46]. The TRPM4 protein was strongly expressed in histological samples of 20 prostate cancer patients, but weak or no expression was seen in benign prostatic hyperplasia tissues [47]. Similarly, in a study of 614 patients, significantly higher TRPM4 staining intensity was found in glands of prostate cancer compared with benign glands [48]. When TRPM4 expression was high, i.e., equal to or above the median histological score, the risk of biochemical recurrence after radical prostatectomy was increased [48]. Another study of 210 prostate cancer patient tissues also demonstrated a positive association between TRPM4 protein expression and local/metastatic progression [27]. On the contrary, increased TRPM4 mRNA expression was only detected in those prostate cancer samples with a Gleason score higher than 7, which is more likely to spread [49]. Both healthy prostate (hPEC) and androgen-insensitive prostate cancer cell lines DU145 and PC3 possessed large TRPM4-mediated Na+ currents [47]. Significantly, store-operated calcium entry increased after siRNA targeting of TRPM4 in hPEC and DU145 cells. TRPM4 KD led to reduced migration but not proliferation of DU145 and PC3 cells, suggesting a role for TRPM4 in cancer cell migration and marking TRPM4 as an anticancer therapeutic target [47]. The mechanism of action by which TRPM4 alters the progression of prostate cancer was also described [50]. Decreasing TRPM4 levels in PC3 cells reduced both total and nuclear localized β-catenin protein levels due to an increase in β-catenin degradation. TRPM4 overexpression in lymph node carcinoma of the prostate cell line increased the total levels of β-catenin, proposing a role for TRPM4 channels in β-catenin oncogene signaling and again enforcing TRPM4 as a new potential target for future therapies in prostate cancer [50]. Not only the proliferation of prostate cancer cells, but also their migration/invasion capability, were influenced by TRPM4. Reducing TRPM4 expression in PC3 cells decreased their migration/invasion capability, possibly due to the reduction in the expression of Snail1, a canonical epithelial to mesenchymal transition (EMT) transcription factor. Inversely, overexpression of TRPM4 in lymph node carcinomas of the prostate cells resulted in increased levels of Snail1 and an increase in its migration potential [49]. Upregulation of miR-150 reduced TRPM4 expression in PC3 cells and resulted in inactivation of the β-catenin signaling pathway, leading to beneficial actions on cancer cells both in vitro (suppression of EMT, proliferation, migration, and invasion) and in vivo (restrained tumor growth and metastasis) [51]. Similarly to previous results, stable CRISPR/Cas9-mediated TRPM4 KO led to lower proliferation, migration, and viability, as well as to reduced cell adhesion and a rounder shape of DU145 cells [27]. Interestingly, despite causing partial inhibition of TRPM4 currents in DU145 cells, the novel inhibitors CBA, NBA, and LBA did not evoke any TRPM4-specific effect in the cellular assays, which questions the role of TRPM4 ion conductivity in cancer hallmark functions in prostate cancer [27].
As mentioned above, the role of TRPM4 in cancer is often based on observations where it exhibits a different expression compared with control tissues; sometimes the correlation between the amount of TRPM4 expression and the prognosis and/or the post-treatment reoccurrence of the disease was studied [35][36][41][48]. Several studies described the molecular mechanisms by which TRPM4 influences these diseases. One mechanism involves TRPM4 activation, which changes the membrane potential, thereby influencing Ca2+ entry by changing the driving force of the Ca2+ influx [47][50]. TRPM4 can co-localize with focal adhesion proteins in mouse embryonic fibroblasts [52] and in commonly used cell lines (HEK and COS-7 cells) [53] to regulate focal adhesion turnover, a process important for cell migration and invasion. TRPM4 channel activity is greatly enhanced by ATP depletion and increases in the intracellular Ca2+ level; both changes are associated with hypoxia, a condition commonly present in cancer cells. Moreover, TRPM4 can play a key role in stemness mediation [54]. Cancer stem cells play roles in chemoresistance, tumor recurrence, and metastasis in breast cancer. TRPM4 inhibition reduced stemness properties of breast cancer stem cells in vitro, therefore TRPM4 can be a novel therapeutic target [54].

5. The Importance of TRPM4 in Central Nervous System (CNS) Pathophysiology

The importance of TRPM4 is greatest in the case of cerebral physiology highlighted by the following: the high number of reviews, the co-expression of TRPM4 with Sulfonylurea Receptor 1 (SUR1) only in the case of pathological conditions, and the very promising actions of TRPM4 inhibition by either pharmacological (using glibenclamide) or other strategies in both experimental models and human CNS pathologies. Some human studies using intravenous glibenclamide administration have already been completed, some are currently enrolling patients. Recent reviews presented not only clinical trials using glibenclamide [55][56], but also the expression and role of SUR1-TRPM4 in CNS injury animal models and in human conditions associated with cerebral edema [56][57]. Apart from TRPM4, other possible drug targets of cerebral edema were also detailed [57][58]. Among these targets is the SUR1-TRPM4 channel complex (and also its complex with the aquaporin4 water channel protein) in astrocytes, which can contribute to swelling [59] but not cell death [60]. Other mechanisms leading to astrocyte swelling were also discussed [61]. It seems that astrocytes are less sensitive to hypoxic-injury-induced oncotic cell death compared with neurons and vascular endothelial cells [62].
SUR1, a per se inactive regulatory subunit of ion channels, can associate with TRPM4 and also with type 6.2 of inward rectifier K+ channel (Kir) to form SUR1-TRPM4 (previously called Sur1-NSCCa-ATP) and adenosine triphosphate-dependent K+ (KATP) channels, respectively [63]. The functional consequence is exactly the opposite in the case of the two channels. Upon activation, SUR1-TRPM4 leads to depolarization, whereas during the activation of KATP channels, it results in the hyperpolarization of cells [64]. In physiological conditions, only KATP channels are present in certain neurons and microglia [65]. On the contrary, SUR1-TRPM4 does not exist normally in the central nervous system, SUR1 was shown to be upregulated in pathological conditions in all cell types (neurons, astrocytes, oligodendrocytes, and endothelium) of the neurovascular unit in the penumbra but not in the necrotic region [66][67][68]. Both the mRNA (Abcc8) and the protein of SUR1 upregulated without the upregulation of Kir6.2 protein or its mRNA (Kcnj11) [66][69]. Recently, the SUR1 content of the cerebrospinal fluid increased variably in some (but not all) pediatric patients with traumatic brain injuries (TBI) [70]. Based on these observations, the other partner of SUR1, TRPM4, was also likely to be expressed. Indeed, this was confirmed on both mRNA and protein levels, not only in animal models [71][72], but also in brain specimens from 15 patients who died within a month of the onset of focal cerebral ischemia [72][73]. TRPM4 expression was also higher after the noxious stimulation of rats in the previously contusion-injured spinal cord [74].
SUR1-TRPM4 channel expression has especially great importance due to the lack of other useful targets in the treatment of cerebral edema which accompanies several CNS pathologies (stroke, TBI, and subarachnoid hemorrhage). In the case of stroke management, many potential targets such as N-methyl-d-aspartate and a-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor antagonists, clomethiazole, antioxidants, citicoline, nitric oxide, immune regulators, therapeutic hypothermia, magnesium, albumin, glibenclamide, and uric acid were discussed [75]. Earlier, potential therapeutic targets for CNS injury management included the inhibition of acid sensing ion channels [76], the Na-K-2Cl symporter with the functionally coupled Na-K ATPase [77], Na-Ca exchanger [78], and vasopressin receptor [79]. A recent review summarizes all ion channels and transporters which can have a proposed role in mediating cerebral edema in acute ischemic stroke and TBI [57]. Moreover, in intracerebral hemorrhage, the potential targets for reducing secondary injury mechanisms were summarized [80]. These previous reviews also highlight the need for a good target and numerous attempts to find a suitable target.
After the CNS injury, the secondary consequences usually culminate in cerebral edema. Only one approved pharmacological treatment exists against the edema: the application of a recombinant tissue plasminogen activator (tPA). Apart from recombinant tPA, decompressive craniectomy can be applied. A craniectomy can reduce the intracranial pressure, which otherwise reduces cerebral blood flow and results in herniation, i.e., life-threatening consequences of high intracranial pressure [81][82]. Surgical intervention, however, is only a symptomatic treatment, and it would be desirable to avoid progression and development of the rise in intracranial pressure. Despite the benefit of a craniectomy, glibenclamide treatment was even more effective in a rat model malignant stroke [67]. Using recombinant tPA can be effective, but it is limited by the short therapeutic window and the possible risk of hemorrhagic conversion [83]. Therefore, tPA is only applied in approximately 20% of patients [84]. Among the many ion channel and transporter targets, SUR1-TRPM4 had the longest therapeutic window [78]. Glibenclamide application was effective upon administration even 10 h after the event in a clinically relevant rat stroke model [85]. Glibenclamide effectively reduced CNS injury-induced harmful consequences in rat [86][87][88][89][90] and mouse animal models [91][92] of TBI from independent labs. Glibenclamide application was also beneficial in stroke models in adult rats [63] and to a certain extent (providing some long-term neuroprotective effect in moderate but not severe hypoxia–ischemia) in neonatal rats too [93]. Glibenclamide administration exerted a beneficial effect on subarachnoid [94][95], but not in intracerebral, hemorrhages [96][97]. In the case of an intracerebral hemorrhage model with aged rats, glibenclamide treatment improved neurological outcomes and ameliorated neuroinflammation [98]. Glibenclamide treatment exerted beneficial actions in a model of hemorrhagic encephalopathy of prematurity [99], just as it did in inflammation-associated conditions of the CNS [94][95][100] and other organs (respiratory, digestive, urological, and cardiac) [101]. Moreover, glibenclamide application was beneficial in HIV infection in vitro [102]. In a mouse model of peripheral nerve injury, glibenclamide-induced inhibition of the newly expressed SUR1 in astrocytes reduced neuropathic pain [103]. Furthermore, glibenclamide treatment reduced the edema and thereby improved the glymphatic flow in status post epilepticus [104]. Likewise, glibenclamide improved the outcome in murine experimental autoimmune encephalomyelitis [105]. It must be noted that the beneficial effect of glibenclamide in stroke models might also be mediated by the blockade of KATP channels on rat CA1 pyramidal neurons in vitro [106] or by the in vivo blockade of microglial KATP channels in rats [68][107][108]. This option was questioned later, as specific antisense oligonucleotides targeted against SUR1 or TRPM4, but not Kir6.1 or Kir6.2 (partners of SUR1 in forming KATP channels), significantly reduced hemispheric swelling in rats in post-ischemic tissues showing co-assembly of SUR1-TRPM4 heteromers [71].
The benefit of glibenclamide was summarized by several publications in stroke [109][110] and spinal cord injury [111] in humans. In a retrospective study, the outcome of stroke in those type 2 diabetic patients continuously on glibenclamide treatment was better compared with those on other medications or suspended glibenclamide treatment [112]. Symptomatic hemorrhagic transformation was found in 0 and 11% of these acute ischemic stroke patients with and without sulfonylurea treatment, respectively [113]. On the contrary, sulfonylurea use before stroke did not influence the outcome compared with other antidiabetic medications [114]. Similarly, while diabetic patients on sulfonylurea treatment showed lower peripheral edema volumes after basal ganglia hemorrhage, their clinical outcome did not improve [115]. Moreover, it was reported that type 2 diabetic patients with sulfonylureas had higher odds ratios for stroke morbidity than those who received comparator drugs [116]. Although glibenclamide applied orally in diabetic patients, application of intravenous glibenclamide could provide more stable plasma levels; it was applied in stroke patients, where it appeared to reduce several surrogate markers of vasogenic edema [117]. Intravenous glibenclamide was well tolerated and free of adverse effects, as reported in two studies GAMES (Glyburide Advantage in Malignant Edema and Stroke)-Pilot and GAMES-RP [118][119] and improved survival in participants ≤70 years of age with large hemispheric infarction [120]. Currently the CHARM (Cirara in large Hemispheric infarction Analyzing modified Rankin and Mortality) trial is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, Phase 3 study which is ongoing to evaluate the efficacy and safety of intravenous glibenclamide for severe cerebral edemas following large hemispheric infarction. Intravenously administered glibenclamide was safe and well tolerated in case of a TBI pilot in a small Phase 2, three-institution, randomized placebo-controlled trial [121]. The treatment reduced hemorrhage volumes and the increase of lesion volumes (hemorrhage plus edema) was much smaller when compared with placebo [121]. ASTRAL (Antagonizing SUR1-TRPM4 to Reduce the progression of intracerebral hematoma and edema surrounding Lesions) is another currently running multicenter, double-blind, multidose, placebo-controlled, randomized, parallel-group, Phase 2 study enrolling only contusion-TBI patients. Jha et al. recently reviewed in detail the clinical and preclinical studies using not only intravenous but also oral glibenclamide in TBI [56].
The effectivity of glibenclamide treatment seems convincing given the facts that: (1) the drug much more potently inhibits SUR1-TRPM4 channels than TRPM4 channels [122]; (2) SUR1-TRPM4 channels are upregulated only in injured CNS tissues [66][95]; (3) glibenclamide treatment has a long therapeutic window [85]; and (4) glibenclamide treatment is free of major side effects (there is a small risk of hypoglycemia, which can be well managed or greatly reduced by intravenous application) [55]. Due to the weak acidic nature of glibenclamide, it is mainly accumulated in the acidic areas of the body [123], which further reduces its potential side effects, as TRPM4 can be present in neurons of various brain areas (see above). Moreover, the inhibitory potential of glibenclamide increases with pH reduction [66]. Fortunately, glibenclamide preferentially inhibits SUR1, as other potential targets such as SUR2 are one to two orders of magnitude less sensitive [124].
In addition to the abovementioned glibenclamide, but the equally effective glimepiride was beneficial—at least in mice with acute ischemic stroke [125]. A previously often-used TRPM4 inhibitor, flufenamic acid, also improved functional recovery in a murine spinal cord injury model [126]. Selective gene suppression of ABCC8 (a gene of SUR1) or TRPM4 applied in spinal cord injury models showed a beneficial effect similar to glibenclamide application [21][69]. Along with that, an obtained KO of either ABCC8 or TRPM4 was protective and prevented capillary fragmentation, halted progressive hemorrhagic necrosis, and prevented the spread of the hemorrhagic contusion [21][69]. TRPM4 KO also reduced cerebral edema and neuronal injury in a murine model of status epilepticus [127]. Antisense oligodeoxynucleotides directed against ABCC8 prevented capillary fragmentation and further accumulation of blood in TBI [87]. These studies emphasize the importance of SUR1-TRPM4 in the pathomechanism of edema formation after CNS injuries.
The role of SUR1-TRPM4 was detailed in several reviews [56][76][128][129]. Briefly, the Na+ influx through newly expressed SUR1-TRPM4 (and other) channels in neurons and astrocytes leads to water influx driven by osmotic gradient in cytotoxic edema. In astrocytes aquaporin-4 water channels can also be involved in SUR1-TRPM4 protein complexes and contribute to cell swelling [59]. Ionic edema formation is facilitated by ion channels, transporters, and newly expressed SUR1-TRPM4 channels on endothelial cells. In the case of vasogenic edema, water and plasma proteins also leave capillaries due to the disruption of the blood–brain barrier. Tight-junction degradation and endothelial cell damage are the reasons for blood–brain barrier damage. Upon complete breakdown of the blood–brain barrier, hemorrhagic conversion occurs, leading to further worsening of the situation. Jha et al. reviewed the molecular mechanisms leading to edema formation [56]. Upstream mechanisms involved in SUR1-TRPM4 upregulation are the hypoxia-inducible factor-1 α, specificity protein 1 [130], and tumor necrosis factor α [87]. Lipopolysaccharide-induced neuroinflammation activated the toll-like receptor 4 and led to de novo upregulation of SUR1-TRPM4. The SUR1-TRPM4-induced depolarization activated calcineurin via induction of low-amplitude repetitive Ca2+ oscillations. Calcineurin dephosphorylates NFATc1, eventually leading to upregulation of nitric oxide synthase-2 mRNA and protein, as well as increased nitric oxide production [131]. Nitric oxide can be converted to harmful peroxynitrite, which can induce protein radical formation [132]. Glibenclamide can evoke a direct antioxidant effect [133]. Blood–brain barrier damage can also occur due to oncotic endothelial cell death [129], mechanisms involving Zonula Occludens-1 disfunction/disruption [91][94], and tPA-induced matrix metalloproteinase-9 production [134].
It appears that SUR1-TRPM4 is indeed a very promising target in the pathological conditions of the CNS. Moreover, serum levels of both SUR1 and TRPM4 can be potential diagnostic markers in the future, at least in aneurysmal subarachnoid hemorrhage [135]. Moreover, a recent study found an association between the progression of intraparenchymal hemorrhages after TBI and 4-4 single-nucleotide variants of ABCC8 and TRPM4 genes [136].
TRPM4 can contribute to glutamate excitotoxicity as TRPM4 and NMDA receptors in extrasynaptic locations are in physical interaction [137]. The NMDA receptor/TRPM4 complex formation is required for excitotoxicity and is mediated by a 57-amino acid intracellular domain and a highly conserved stretch of 18 amino acids of TRPM4 and NMDA receptor (GluN2A and GluN2B, respectively). In mouse models of stroke and retinal degeneration, the inhibition of the TRPM4-interacting domain, called TwinF, by small molecular inhibitors proved to reduce excitotoxicity without impairing the function of synaptic NMDA receptors [137].
For a comprehensive review on the role of sulfonylurea receptor 1 in central nervous system injury see the work of Jha et al. [138].

6. The Pathophysiological Role of TRPM4 in the Skin

Two TRPM4 missense mutations leading to increased activation gating and enhanced Ca2+ sensitivity were reported to cause an autosomal dominant form of progressive symmetric erythrokeratodermia [139]. In keratinocytes overexpressing those TRPM4 mutants, enhanced proliferation and up-regulation of proliferation and differentiation markers were detected. The transient receptor potential melastatin 4 (TRPM4) channel plays a significant role in regulating immune responses in keratinocytes, the predominant cell type in the epidermis. TRPM4 is known to be involved in the modulation of cytokine production. Activation of TRPM4, using the agonist BTP2, significantly reduced cytokine production, such as IL-1α and IL-6, in keratinocytes treated with tumor necrosis factor-alpha (TNF-α). This cytokine suppression was not observed in TRPM4-deficient cells, highlighting the channel's role in cytokine regulation [140].

7. Involvement of TRPM4 in Cardiac Disorders

7.1. The Role of TRPM4 in Cardiac Hypertrophy and Heart Failure

Although the causative link between TRPM4 mutations and conduction problems is clearly established, TRPM4 can also be involved in other cardiac problems [141][142] such as cardiac hypertrophy [143][144]. For instance, higher TRPM4 expression was shown in hypertrophied ventricular cells obtained from the hearts of spontaneously hypertensive rats compared with control Wistar–Kyoto rats [145]. Moreover, in the case of dedifferentiated cultured rat ventricular cardiomyocytes with similar characteristics to hypertrophied cells, TRPM4 could be detected, while it was absent in freshly isolated ventricular cells [146]. TRPM4 (together with other mechanisms) can contribute to arrhythmias (by delayed afterdepolarization (DAD) generation), especially in Ca2+ overloaded cells [147].
On the contrary, TRPM4 has a protective role in hypertensive hypertrophy and heart failure in mice as (1) TRPM4 KO mice are hypertensive due to an increased catecholamine release [148]; (2) their β-adrenergic inotropic response in ventricular myocardium was increased compared with wild type counterparts [149]; (3) angiotensin II-induced cardiac hypertrophy was more pronounced in KO vs. wild type mice [150]; and (4) left ventricular eccentric hypertrophy with an increase in both wall thickness and chamber size was detected in the adult TRPM4 KO mice, compared with wild type littermate controls [151]. TRPM4 expression in right ventricles was reduced in a rat model of pulmonary hypertension, and right ventricular hypertrophy was more severe when TRPM4 was absent (TRPM4 KO) compared with wild type animals [152].
In contrast, TRPM4 can act as a positive regulator of pressure-overload induced left ventricular hypertrophy as selective deletion of TRPM4 in mouse cardiomyocytes resulted in an approximately 50% reduction of left ventricular hypertrophy induced by transverse aortic constriction [153].
In the case of humans, TRPM4 mRNA levels were 65% higher in left ventricular tissue samples of patients with end-stage heart failure (NYHA III–IV), compared with those obtained from healthy control subjects [154]. There was, however, no correlation between the TRPM4 mRNA level and either gender or the clinical, biochemical, and functional parameters of the heart. Nevertheless, TRPM4 protein expression was also higher (about twice as much) in human left ventricular tissue samples of heart failure patients compared with samples from healthy donor hearts [155]. For this larger tissue expression, the higher TRPM4 currents in cardiac fibroblasts could be responsible, although the contribution of ventricular myocytes cannot be excluded, as those cells were not studied [155].

7.2. The Role of TRPM4 in Ischemia-Reperfusion Injury

Unlike with cardiac hypertrophy induced by hypertension, TRPM4 mRNA remained unchanged during both 25 min of ischemia and the following 40-min-long reperfusion in rats [156]. Nevertheless, the inhibition of TRPM4 reduced hypoxia-reperfusion-induced EAD formation in murine isolated right ventricular muscle, especially during reperfusion [157]. The frequency of EADs was greatly and dose-dependently abolished by the TRPM4 inhibitor 9-phenanthrol (and flufenamic acid) [157]. Similarly, pretreatment with 9-phenanthrol dramatically improved contractile function recovery during reperfusion of rat hearts and significantly reduced the infarcted area size [158]. Furthermore, in H9c2 cardiomyocytes, H2O2-evoked reactive oxygen species-induced injury was reduced not only by 9-phenanthrol pretreatment but also TRPM4 silencing [159]. The mechanism behind the harmful action of TRPM4 in that cell line might involve the reduction of mitochondrial membrane potential and intracellular ATP levels (as well as the intracellular Ca2+ overload), as those were absent in TRPM4 KO H9c2 cells [160]. TRPM4 can be responsible for the generation of not only EADs, but also DADs, a possible mechanism explaining the higher incidence of death upon isoprenaline-induced β-adrenergic stimulation in wild type animals compared with those of TRPM4 KO in a murine ischemic heart failure model [161]. Of note, basal cardiac parameters were not different between the wild type and KO mice. Computational modeling also highlighted the role of TRPM4 in EAD generation [162]. In vivo TRPM4 overexpression increased the vulnerability to premature ventricular ectopic beats during exercise-induced β-adrenergic stress [163]. In contrast, TRPM4 was beneficial; moreover, it was essential for survival in a mouse model of myocardial infarction [164]. Unlike unaltered TRPM4 mRNA expression in rats [156], murine TRPM4 expression increased at both the mRNA and protein levels in a mouse model of myocardial infarction [164].

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