Receptor Potential Cation Channel Subfamily Research Articles

Sulfated Progesterone Metabolites That Enhance Insulin Secretion via TRPM3 Are Reduced in Serum From Women With Gestational Diabetes Mellitus.

Serum progesterone sulfates were evaluated in the etiology of gestational diabetes mellitus (GDM). Serum progesterone sulfates were measured using ultra-performance liquid chromatography–tandem mass spectrometry in four patient cohorts: 1) the Hyperglycemia and Adverse Pregnancy Outcomes study; 2) London-based women of mixed ancestry and 3) U.K.-based women of European ancestry with or without GDM; and 4) 11–13 weeks pregnant women with BMI ≤25 or BMI ≥35 kg/m2 with subsequent uncomplicated pregnancies or GDM. Glucose-stimulated insulin secretion (GSIS) was evaluated in response to progesterone sulfates in mouse islets and human islets. Calcium fluorescence was measured in HEK293 cells expressing transient receptor potential cation channel subfamily M member 3 (TRPM3). Computer modeling using Molecular Operating Environment generated three-dimensional structures of TRPM3. Epiallopregnanolone sulfate (PM5S) concentrations were reduced in GDM (P < 0.05), in women with higher fasting plasma glucose (P < 0.010), and in early pregnancy samples from women who subsequently developed GDM with BMI ≥35 kg/m2 (P < 0.05). In islets, 50 µmol/L PM5S increased GSIS by at least twofold (P < 0.001); isosakuranetin (TRPM3 inhibitor) abolished this effect. PM5S increased calcium influx in TRPM3-expressing HEK293 cells. Computer modeling and docking showed identical positioning of PM5S to the natural ligand in TRPM3. PM5S increases GSIS and is reduced in GDM serum. The activation of GSIS by PM5S is mediated by TRPM3 in both mouse and human islets.

TRPM2 Is Not Required for T-Cell Activation and Differentiation.

Antigen recognition by the T-cell receptor induces a cytosolic Ca2+ signal that is crucial for T-cell function. The Ca2+ channel TRPM2 (transient receptor potential cation channel subfamily M member 2) has been shown to facilitate influx of extracellular Ca2+ through the plasma membrane of T cells. Therefore, it was suggested that TRPM2 is involved in T-cell activation and differentiation. However, these results are largely derived from in vitro studies using T-cell lines and non-physiologic means of TRPM2 activation. Thus, the relevance of TRPM2-mediated Ca2+ signaling in T cells remains unclear. Here, we use TRPM2-deficient mice to investigate the function of TRPM2 in T-cell activation and differentiation. In response to TCR stimulation in vitro, Trpm2 -/- and WT CD4+ and CD8+ T cells similarly upregulated the early activation markers NUR77, IRF4, and CD69. We also observed regular proliferation of Trpm2 -/- CD8+ T cells and unimpaired differentiation of CD4+ T cells into Th1, Th17, and Treg cells under specific polarizing conditions. In vivo, Trpm2 -/- and WT CD8+ T cells showed equal specific responses to Listeria monocytogenes after infection of WT and Trpm2 -/- mice and after transfer of WT and Trpm2 -/- CD8+ T cells into infected recipients. CD4+ T-cell responses were investigated in the model of anti-CD3 mAb-induced intestinal inflammation, which allows analysis of Th1, Th17, Treg, and Tr1-cell differentiation. Here again, we detected similar responses of WT and Trpm2 -/- CD4+ T cells. In conclusion, our results argue against a major function of TRPM2 in T-cell activation and differentiation.

NFKB1 Signalling Activation Contributes to TRPV1 Over-expression via Repressing MiR-375 and MiR-455: a Study on Neuropathic Low Back Pain

Transient receptor potential cation channel subfamily V member 1 (TRPV1) has been found over-expressed in low back pain (LBP) patients with neuropathic pain (NP), but the underlying mechanism is still unclear. In the present study, the up-regulation of the TRPV1 protein level in sinuvertebral nerve biopsies from patients with NP was verified by immunoblotting, but the TRPV1 mRNA level was not significantly changed. MiRNAs targeting TRPV1 mRNA were predicted by a bioinformatic tool, and the interactions between the miRNAs and TRPV1 were confirmed by dual luciferase assay. The correlation between NFKB1 signalling and TRPV1 expression was analysed and confirmed by using sNF96.2 cells after lipopolysaccharide stimulation. We found that five out of 18 miRNAs repressed TRPV1 expression, and the levels of miR-375 and miR-455 were negatively correlated with the protein level of TRPV1 in patients with NP. MiR-375 and miR-455 were identified to repress TRPV1 expression via targeting the 3’UTR of TRPV1 mRNA. NFKB1 signalling activation down-regulated the expression of miR-375 and miR-455, and thus up-regulated the TRPV1 protein level. In conclusion, we partially unveiled the mechanism of how TRPV1 is over-expressed in chronic LBP patients with NP and provided two potential candidate miRNAs for NP treatment.

N-Methylamide-structured SB366791 derivatives with high TRPV1 antagonistic activity: toward PET radiotracers to visualize TRPV1.

Transient receptor potential cation channel subfamily V member 1 (TRPV1)-targeted compounds were synthesized by modifying the structure of SB366791, a pharmaceutically representative TRPV1 antagonist. To avoid amide-iminol tautomerization, structurally supported N-methylated amides (i.e., 3-alkoxy-substitued N-meythylamide derivatives of SB366791) were evaluated using a Ca2+ influx assay, in which cells expressed recombinant TRPV1 in the presence of 1.0 μM capsaicin. The antagonistic activities of N-(3-methoxyphenyl)-N-methyl-4-chlorocinnamamide (2) (RLC-TV1004) and N-{3-(3-fluoropropoxy)phenyl}-N-methyl-4-chlorocinnamamide (4) (RLC-TV1006) were found to be approximately three-fold higher (IC50: 1.3 μM and 1.1 μM, respectively) than that of SB366791 (IC50: 3.7 μM). These results will help reinvigorate the potential of SB366791 in medicinal chemistry applications. The 3-methoxy and 3-fluoroalkoxy substituents were used to obtain radioactive [11C]methoxy- or [18F]fluoroalkoxy-incorporated tracers for in vivo positron emission tomography (PET). Using the 11C- or 18F-labeled derivatives, explorative PET imaging trials were performed in rats.

Noninvasive near-infrared light triggers the remote activation of thermo-responsive TRPV1 channels in neurons based on biodegradable/photothermal polymer micelles.

In this study, we developed a novel biodegradable/photothermal polymer micelle-based remote-activation method for a temperature-sensitive ion channel, namely transient receptor potential cation channel subfamily V member 1 (TRPV1). Biodegradable/photothermal polymer micelles containing indocyanine green (ICG-micelles) were prepared using a simple one-pod mixing method. The obtained ICG-micelles showed biocompatibility and biodegradability. Furthermore, under tissue-penetrable near-infrared (NIR) laser irradiation, the ICG-micelles exhibited excellent photothermal effects and NIR emission. Moreover, NIR light-induced remote activation of neurons was successfully performed. ICG-micelles loaded with anti-TRPV1 antibodies effectively bound TRPV1 on cell membranes, and accelerated Ca2+ ion influx into neuronal cells was induced under NIR irradiation. Based on these findings, it is anticipated that the ICG-micelles can serve as a novel noninvasive remote-activation tool for neuronal cells.

TRPV1 is a potential biomarker for the prediction and treatment of multiple cancers based on a pan-cancer analysis.

Transient receptor potential cation channel subfamily V member 1 (TRPV1) was considered to play pivotal roles in multiple cancers; however, the expression and clinical significance of the TRPV1 remain unclear, which were explored in this study. The pan-cancer analysis was performed based on 10,236 samples in 32 cancers. Differential TRPV1 expression levels were detected in 12 cancers (p < 0.05). TRPV1 demonstrated its conspicuous prognosis significance and prediction effects for some cancers (e.g., lung adenocarcinoma), indicating its potential as a valuable and novel biomarker in treating and predicting cancers. TRPV1 expression was relevant to DNA methyltransferases, mismatch repair genes, tumor mutational burden, and microsatellite instability. TRPV1 expression was associated with the immune microenvironment of some cancers, and its roles in different cancers may be mediated by affecting various immune cells. Gene set enrichment analysis discloses the significant relevance of TRPV1 expression with a series of metabolic and immunoregulatory-related pathways. This study provided a comprehensive workflow of the expression, clinical significance, and underlying mechanisms of TRPV1 in pan-cancer. TRPV1 may be an underlying biomarker for predicting and treating multiple cancer.

Transient Receptor Potential Cation Channel Subfamily V Member 4 Mediates Pyroptosis in Chronic Obstructive Pulmonary Disease.

TRPV4, a calcium permeable cation selective channel, was found to be involved in chronic obstructive pulmonary disease (COPD) through releasing ATP and IL-1β. Pyroptosis, a newly discovered pro-inflammatory cell death, was induced by cigarette smoke (CS) in airway epithelial cells (AECs). More recent studies indicated that blocking Ca2+ influx effectively inhibited pyroptosis. Therefore, we asked whether TRPV4 mediated CS-induced pyroptosis of AECs and hence participated in the pathogenesis of COPD. We found that pyroptosis and TRPV4 were upregulated in AECs from patients with COPD and long-term CS-exposed mice. Moreover, pharmacological inhibition or knockdown of TRPV4 function alleviated CS extract (CSE)-induced pyroptosis by inhibiting NACHT, LRP, PYD domains-containing protein 3 (NLRP3) inflammasome/activated caspase-1/gasdermin D pathway, decreasing the number of PI positive cells and lactate dehydrogenase (LDH) release, decreasing the expression of pro- inflammatory interleukin gene (IL)-1β, IL-8, and IL-18 expression, as well as increasing anti-inflammatory gene expression [NAD(P)H quinone dehydrogenase 1 (NQO1), superoxide dismutase 2 (mitochondrial) (MNSOD), and catalase, (CAT)]. Moreover, pharmacological inhibition or knockdown of TRPV4 function significantly relieved CSE-induced mitochondrial damage including decreased mitochondrial membrane potential, mitochondrial fusion protein (OPA1, MFN2) expression, and increased mitochondrial fission protein (DRP1, MFF) expression. Taken together, these findings indicate that TRPV4 mediates AEC pyroptosis via NLRP3/caspase-1/GSDMD pathway in COPD.

Evaluation of Serum Levels of Transient Receptor Potential Cation Channel Subfamily V Member 1, Vasoactive Intestinal Polypeptide, and Pituitary Adenylate Cyclase-Activating Polypeptide in Chronic and Episodic Migraine: The Possible Role in Migraine Transformation.

Objectives: This study aimed to investigate the role of serum levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), vasoacive intestinal peptide (VIP), and pituitary adenylate cyclase-activating polypeptide (PACAP) in the development and also the transformation of migraine in patients suffering from migraine.Methods: Eighty-nine participants with a mean age of 39 years were divided into 23 episodic migraine (EM), 36 chronic migraine (CM), and 30 healthy control groups. Demographic, anthropometric, and headache characteristic information, and also blood samples, was collected. Serum levels of TRPV1, VIP, and PACAP were measured using the enzyme-linked immunosorbent assay (ELISA) technique.Results: Based on our findings, the serum level of TRPV1 was significantly higher in CM compared to the control group (p < 0.05), whereas serum levels of VIP (p < 0.01) and PACAP (p < 0.05) in the EM group were significantly more than the control group. There was no significant difference between EM and CM groups.Conclusions: An elevation in the serum levels of TRVP1 among chronic migraineurs and increments in the levels of VIP and PACAP were observed among EM patients compared to healthy subjects. However, our data failed to demonstrate the probable role of these biomarkers in migraine progression, and more studies are needed to clarify the molecular mechanisms involved in migraine progression.

Update on the role of noncoding RNAs in vitiligo.

Update on the role of noncoding RNAs in vitiligo.

The Anti-Inflammatory and Anti-Pruritus Mechanisms of Huanglian Jiedu Decoction in the Treatment of Atopic Dermatitis.

Atopic dermatitis (AD) is a common chronic skin disease driven by a T-cell-mediated immune response, with inflammation and pruritus being its main clinical manifestations. Huanglian Jiedu decoction (HLJDT), which is an ancient Chinese medicine herbal formula derived from Wai-Tai-Mi-Yao, is a potentially effective treatment for AD. We aimed to clarify the anti-inflammatory and anti-pruritus mechanisms of HLJDT in AD treatment. We performed immunohistochemistry, Western blotting, reverse transcriptase-polymerase chain reaction, Luminex-based direct multiplex immunoassay, enzyme-linked immunosorbent assays, and flow cytometry to address the abovementioned aims. HLJDT significantly reduced clinical symptoms and ear swelling in AD-like mice by inhibiting the production of cytokines [histamine, interleukin (IL)-3, IL-4, IL-5, IL-13, IL-17A, IL-31, and IL-33], substance P (SP), transient receptor potential cation channel subfamily V member 1 (TRPV-1), and gastrin-releasing peptide (GRP). Additionally, HLJDT significantly suppressed the protein expression levels and positive cell percentage of CD28, CD80, CD86, CD207, CD326, MHCII, and OX40 in the lymphoid nodes. Moreover, HLJDT significantly suppressed mRNA and protein expression of tyrosine–protein kinase (JAK1), histamine H4 receptor, and IL-4Rα, as well as the protein expression of GRP, SP, and TRPV-1 in the root ganglion. Our findings indicate that HLJDT can treat AD by regulating the antigen presentation function of dendritic cells, weakening T-lymphocyte activation, and subsequently exerting anti-inflammatory and anti-pruritus effects.

Cutaneous Neuroimmune Interactions of TSLP and TRPV4 Play Pivotal Roles in Dry Skin-Induced Pruritus.

Dry skin is a symptom of skin barrier dysfunction that evokes pruritus; however, the cutaneous neuroimmune interactions underlying dry skin-induced pruritus remain unclear. Therefore, we aimed to elucidate the mechanisms underlying dry skin-induced pruritus. To this end, an acetone/ethanol/water (AEW)-induced mouse model of dry skin was used in this study. We observed that the production of thymic stromal lymphopoietin (TSLP) significantly increased in the keratinocytes of AEW mice. Importantly, treatment with an antagonist of transient receptor potential cation channel subfamily V member 4 (TRPV4), HC067047, ameliorated dry skin conditions in AEW mice. The symptoms of dry skin were significantly reduced in Trpv4 knockout (KO) mice following treatment with AEW. The increase in the intracellular calcium levels by TSLP in the dorsal root ganglia (DRG) of Trpv4 KO mice was also significantly attenuated. The spontaneous scratching bouts were significantly decreased in both the HC067047-treated and Trpv4 KO AEW mice. Importantly, the TSLP-dependent release of tryptase from the mast cells was significantly reduced in both the HC067047-treated mice and Trpv4 KO AEW mice. Notably, inhibition of the TSLP-induced signaling pathway in DRG selectively reduced the spontaneous scratching bouts in AEW mice. Overall, the results demonstrated that the cutaneous neuroimmune interactions of TSLP and TRPV4 play pivotal roles in dry skin-induced pruritus.

Toxic Peptide From Palythoa caribaeorum Acting on the TRPV1 Channel Prevents Pentylenetetrazol-Induced Epilepsy in Zebrafish Larvae.

PcActx peptide, identified from the transcriptome of zoantharian Palythoa caribaeorum, was clustered into the phylogeny of analgesic polypeptides from sea anemone Heteractis crispa (known as APHC peptides). APHC peptides were considered as inhibitors of transient receptor potential cation channel subfamily V member 1 (TRPV1). TRPV1 is a calcium-permeable channel expressed in epileptic brain areas, serving as a potential target for preventing epileptic seizures. Through in silico and in vitro analysis, PcActx peptide was shown to be a potential TRPV1 channel blocker. In vivo studies showed that the linear and oxidized PcActx peptides caused concentration-dependent increases in mortality of zebrafish larvae. However, monotreatment with PcActx peptides below the maximum tolerated doses (MTD) did not affect locomotor behavior. Moreover, PcActx peptides (both linear and oxidized forms) could effectively reverse pentylenetetrazol (PTZ)-induced seizure-related behavior in zebrafish larvae and prevent overexpression of c-fos and npas4a at the mRNA level. The excessive production of ROS induced by PTZ was markedly attenuated by both linear and oxidized PcActx peptides. It was also verified that the oxidized PcActx peptide was more effective than the linear one. In particular, oxidized PcActx peptide notably modulated the mRNA expression of genes involved in calcium signaling and γ-aminobutyric acid (GABA)ergic-glutamatergic signaling, including calb1, calb2, gabra1, grm1, gria1b, grin2b, gat1, slc1a2b, gad1b, and glsa. Taken together, PcActx peptide, as a novel neuroactive peptide, exhibits prominent anti-epileptic activity, probably through modulating calcium signaling and GABAergic-glutamatergic signaling, and is a promising candidate for epilepsy management.

Establishment of the menthol test as a clinical evaluation method for oxaliplatin-induced neuropathy.

To determine whether the tongue menthol test, which measures the cold sensation detection threshold (CDT) of the tongue, used before and after oxaliplatin administration is an objective evaluation method for oxaliplatin-induced peripheral neuropathy (OPN). The tongue menthol test was administered to patients both before and after undergoing chemotherapy containing oxaliplatin for colorectal cancer. The tongue menthol test was conducted by applying a menthol solution (a selective agonist of transient receptor potential cation channel subfamily M member 8 [TRPM8]) to the tongue and measuring the CDT. The mean CDT before the first dose of oxaliplatin was 0.34% (0.005%-1%; n=38), and the mean CDT after the first dose was 0.32% (0.005%-1%; n=38). The CDT appeared to decrease after the first dose, but this difference was not significant. In patients who received five courses of oxaliplatin, changes in CDT values were compared before and after the five courses. In patients with Neurotoxicity Criteria of Debiopharm (DEB-NTC) grade 2 neuropathy, the pre-oxaliplatin administration CDT was compared between before grade exacerbation and when exacerbation occurred, and was found to decline when grade exacerbation occurred. Moreover, when the CDTs before and after administration were compared before grade exacerbation, there was a significant decrease in CDT after administration (P=0.04). By performing a menthol test in oxaliplatin-treated patients, it may be possible to objectively predict the exacerbation of peripheral neuropathy at an early stage.

Abstract 8997: TRPM7 Mediates Hypomagnesemia-Induced Mitochondrial Dysfunction, Diastolic Heart Failure, and Death

Introduction: Hypomagnesemia (HypoMg) induces mitochondrial dysfunction accompanied by disturbed Mg homeostasis in mouse hearts. Transient receptor potential cation channel subfamily M 7 (TRPM7) is a Mg transporter with both channel and kinase function located in the plasma membrane. Its upregulation has been observed in HypoMg. We investigated the role of TRPM7 in mitochondrial dysfunction mediated by HypoMg. Methods: Wild type (WT) C57BL/6J mice and transgenic mice with a K1646R mutation in the TRPM7 kinase domain (TRPM7 K1646R , with no kinase function) were fed with a low-Mg diet (HypoMg mice, 15-30 mg/kg Mg) or a normal Mg diet (control mice, 600 mg/kg Mg) for 6 weeks. Human cardiac RL-14 cells were cultured in a normal (with 0.81 mM MgSO 4 ) or a low-Mg medium (customized medium with 0.04 mM MgSO 4 ) for 48 h. TRPM7 knockdown was achieved by siRNA in RL-14 cells. Results: WT HypoMg mice showed significantly decreased serum Mg, diastolic dysfunction, increased mitochondrial ROS in isolated cardiomyocytes, increased TRPM7 mRNA and protein level, decreased ATP production and decreased total mitochondrial Mg content in heart tissues. TRPM7 K1646R mice on the low-Mg diet showed normal diastolic function, normal mitochondrial ROS levels in cardiomyocytes, and recovered ATP production and mitochondrial Mg content in hearts. Furthermore, TRPM7 K1646R prevent HypoMg-induced seizures and death (64.8% death in WT HypoMg mice). Hypomagnesemia in RL-14 cells resulted in increased mitochondrial ROS (1.77±0.08-fold of control, P&lt;0.0001), which was suppressed to 0.86±0.04-fold of control by TRPM7 siRNA (25-30% TRPM7 reduction confirmed by RT-PCR and Western blot). Conclusions: HypoMg induces elevation of TRPM7 protein expression, and TRPM7 is involved in mitochondrial dysfunction, diastolic dysfunction, and death associated with HypoMg.

Midbrain Dopamine Neurons Defined by TrpV1 Modulate Psychomotor Behavior.

Dopamine (DA) neurons of the ventral tegmental area (VTA) continue to gain attention as far more heterogeneous than previously realized. Within the medial aspect of the VTA, the unexpected presence of TrpV1 mRNA has been identified. TrpV1 encodes the Transient Receptor Potential cation channel subfamily V member 1, TRPV1, also known as the capsaicin receptor, well recognized for its role in heat and pain processing by peripheral neurons. In contrast, the brain distribution of TrpV1 has been debated. Here, we hypothesized that the TrpV1+ identity defines a distinct subpopulation of VTA DA neurons. To explore these brain TrpV1+ neurons, histological analyses and Cre-driven mouse genetics were employed. TrpV1 mRNA was most strongly detected at the perinatal stage forming a band of scattered neurons throughout the medial VTA, reaching into the posterior hypothalamus. Within the VTA, the majority of TrpV1 co-localized with both Tyrosine hydroxylase (Th) and Vesicular monoamine transporter 2 (Vmat2), confirming a DA phenotype. However, TrpV1 also co-localized substantially with Vesicular glutamate transporter 2 (Vglut2), representing the capacity for glutamate (GLU) release. These TrpV1+/Th+/Vglut2+/Vmat2+ neurons thus constitute a molecularly and anatomically distinct subpopulation of DA-GLU co-releasing neurons. To assess behavioral impact, a TrpV1Cre-driven strategy targeting the Vmat2 gene in mice was implemented. This manipulation was sufficient to alter psychomotor behavior induced by amphetamine. The acute effect of the drug was accentuated above control levels, suggesting super-sensitivity in the drug-na ve state resembling a “pre-sensitized” phenotype. However, no progressive increase with repeated injections was observed. This study identifies a distinct TrpV1+ VTA subpopulation as a critical modulatory component in responsiveness to amphetamine. Moreover, expression of the gene encoding TRPV1 in selected VTA neurons opens up for new possibilities in pharmacological intervention of this heterogeneous, but clinically important, brain area.

L-Menthol-Loadable Electrospun Fibers of PMVEMA Anhydride for Topical Administration.

Poly(methyl vinyl ether-alt-maleic anhydride) (PMVEMA) of 119 and 139 molecular weights (P119 and P139, respectively) were electrospun to evaluate the resulting fibers as a topical delivery vehicle for (L-)menthol. Thus, electrospinning parameters were optimized for the production of uniform bead-free fibers from 12% w/w PMVEMA (±2.3% w/w menthol) solutions, and their morphology and size were characterized by field emission scanning electron microscopy (FESEM). The fibers of P119 (F119s) and P139 (F139s) showed average diameter sizes of approximately 534 and 664 nm, respectively, when unloaded, and 837 and 1369 nm when loaded with menthol. The morphology of all types of fibers was cylindrical except for F139s, which mostly displayed a double-ribbon-like shape. Gas chromatography-mass spectrometry (GC-MS) analysis determined that not only was the menthol encapsulation efficiency higher in F139s (92% versus 68% in F119s) but also that its stability over time was higher, given that in contrast with F119s, no significant losses in encapsulated menthol were detected in the F139s after 10 days post-production. Finally, in vitro biological assays showed no significant induction of cytotoxicity for any of the experimental fibers or in the full functionality of the encapsulated menthol, as it achieved equivalent free-menthol levels of activation of its specific receptor, the (human) transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8).

Zinc Inhibits Cadherin 1 Expression Induced by 1α,25-Dihydroxyvitamin D3 in Colon Cancer Cells.

Zinc is a mineral that is essential for biological molecules, such as transcription factors, and is involved in the maintenance of intestinal homeostasis. Vitamin D signaling is mediated by vitamin D receptor (VDR) activated by 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] and is also important in intestinal functions, such as calcium absorption and epithelial barrier maintenance. However, the crosstalk between vitamin D signaling and zinc signaling in intestinal cells remains poorly understood. Colon cancer SW480 and HCT116 cells were treated with zinc chloride (ZnCl2) with/without 1,25(OH)2D3 Expression of zinc-inducible genes [metallothionein 1A (MT1A) and MT2A] and VDR target genes [cytochrome P450 family 24 subfamily A member 1 (CYP24A1), transient receptor potential cation channel subfamily V member 6 (TRPV6) and cadherin 1 (CDH1)] was examined. Treatment of cells with ZnCl2 effectively induced MT1A and MT2A mRNA expression, and interestingly suppressed mRNA expression of CDH1, which was induced by 1,25(OH)2D3 in both cell lines. ZnCl2 also reduced the CDH1 protein level in HCT116 cells. Zinc signaling suppresses VDR-induced expression of CDH1.

Transient Receptor Potential Channel 4 Small-Molecule Inhibition Alleviates Migraine-Like Behavior in Mice.

Migraine is a common neurological disorder with few available treatment options. Recently, we have demonstrated the role of transient receptor potential cation channel subfamily C member 4 (TRPC4) in itch and the modulation of the calcitonin gene-related peptide (CGRP), a biomarker and emerging therapeutic target for migraine. In this study, we characterized the role of TRPC4 in pain and evaluated its inhibition as anti-migraine pain therapy in preclinical mouse models. First, we found that TRPC4 is highly expressed in trigeminal ganglia and its activation not only mediates itch but also pain. Second, we demonstrated that the small-molecule inhibitor ML204, a specific TRPC4 antagonist, significantly reduced episodic and chronic migraine-like behaviors in male and female mice after injection of nitroglycerin (NTG), a well-known migraine inducer in rodents and humans. Third, we found a significant decrease in CGRP protein levels in the plasma of both male and female mice treated with ML-204, which largely prevented the development of chronic migraine-like behavior. Using sensory neuron cultures, we confirmed that activation of TRPC4 elicited release of CGRP, which was significantly diminished by ML-204. Collectively, our findings identify TRPC4 in peripheral sensory neurons as a mediator of CGRP release and NTG-evoked migraine. Since a TRPC4 antagonist is already in clinical trials, we expect that this study will rapidly lead to novel and effective clinical treatments for migraineurs.

Sacubitril Ameliorates Cardiac Fibrosis Through Inhibiting TRPM7 Channel.

Heart failure caused by cardiac fibrosis has become a major challenge of public health worldwide. Cardiomyocyte programmed cell death (PCD) and activation of fibroblasts are crucial pathological features, both of which are associated with aberrant Ca2+ influx. Transient receptor potential cation channel subfamily M member 7 (TRPM7), the major Ca2+ permeable channel, plays a regulatory role in cardiac fibrosis. In this study, we sought to explore the mechanistic details for sacubitril, a component of sacubitril/valsartan, in treating cardiac fibrosis. We demonstrated that sacubitril/valsartan could effectively ameliorate cardiac dysfunction and reduce cardiac fibrosis induced by isoprotereno (ISO) in vivo. We further investigated the anti-fibrotic effect of sacubitril in fibroblasts. LBQ657, the metabolite of sacubitril, could significantly attenuate transforming growth factor-β 1 (TGF-β1) induced cardiac fibrosis by blocking TRPM7 channel, rather than suppressing its protein expression. In addition, LBQ657 reduced hypoxia-induced cardiomyocyte PCD via suppression of Ca2+ influx regulated by TRPM7. These findings suggested that sacubitril ameliorated cardiac fibrosis by acting on both fibroblasts and cardiomyocytes through inhibiting TRPM7 channel.

TRPV4 is activated by mechanical stimulation to induce prostaglandins release in trabecular meshwork, lowering intraocular pressure.

Trabecular meshwork constitutes the conventional outflow pathway and controls intraocular pressure by regulating aqueous outflow. Mechanical stimulation has been studied as one of the triggers to regulate aqueous outflow in trabecular meshwork, but it is not well understood. We investigated that how transient receptor potential cation channel subfamily V member 4 (TRPV4) functions in human trabecular meshwork cells (HTMC) and affects intraocular pressure (IOP). HTMC were treated with TRPV4 siRNA, followed by incubation for 24 hours. We confirmed the suppression of TRPV4 mRNA expression and the reduction of Ca2+ influx by the TRPV4 agonist GSK1016790A in TRPV4 siRNA-treated HTMC. TRPV4 siRNA-treated HTMC exhibited a significant reduction in Ca2+ influx and production of arachidonic acid and prostaglandin (PG) E2 induced by mechanical stretch, and direct activation of TRPV4 by GSK1016790A increased production of arachidonic acid, PGE2, and PGD2 and inhibited gel contraction. Furthermore, TRPV4-deficient mice had higher IOP than wild-type mice, and GSK1016790A administration lowered IOP. These results suggest that TRPV4 mediates the cellular response induced by trabecular meshwork stretch, leading to IOP reduction through the production of prostaglandins and inhibition of cell contraction. Targeting TRPV4 may have therapeutic benefits that lead to lowering IOP in glaucoma patients.