Transient Receptor Potential Channel Proteins Research Articles

FGF13 enhances the function of TRPV1 by stabilizing microtubules and regulates acute and chronic itch.

Itching is an aversive somatosensation that triggers the desire to scratch. Transient receptor potential (TRP) channel proteins are key players in acute and chronic itch. However, whether the modulatory effect of fibroblast growth factor 13 (FGF13) on acute and chronic itch is associated with TRP channel proteins is unclear. Here, we demonstrated that conditional knockout of Fgf13 in dorsal root ganglion neurons induced significant impairment in scratching behaviors in response to acute histamine-dependent and chronic dry skin itch models. Furthermore, FGF13 selectively regulated the function of the TRPV1, but not the TRPA1 channel on Ca2+ imaging and electrophysiological recordings, as demonstrated by a significant reduction in neuronal excitability and current density induced by TRPV1 channel activation, whereas TRPA1 channel activation had no effect. Changes in channel currents were also verified in HEK cell lines. Subsequently, we observed that selective modulation of TRPV1 by FGF13 required its microtubule-stabilizing effect. Furthermore, in FGF13 knockout mice, only the overexpression of FGF13 with a tubulin-binding domain could rescue TRP channel function and the impaired itch behavior. Our findings reveal a novel mechanism by which FGF13 is involved in TRPV1-dependent itch transduction and provide valuable clues for alleviating pathological itch syndrome.

High-throughput screening of transient receptor potential (TRP) channels in pterygium.

Pterygium is a hyaline degenerative disease of the conjunctiva characterized by the progression of fibrovascular connective tissue from the bulbar conjunctiva to the cornea. The mechanism of pterygium formation is still not fully understood. Transient receptor potential (TRP) channels are a group of ion channels with distinct characteristics. Recent indications suggest TRP channels may play a significant regulatory role in pterygium development, but previous studies have mainly focused on in silico analysis. Accordingly, in the present study, we aimed to decipher the expression signatures and role of TRP channels in pterygium development. The study encompassed a cohort of 45 patients matched for age and gender distribution, comprising 30 individuals with primary pterygium (PP) and 15 individuals with recurrent pterygium(RP). The control group consisted of unaffected conjunctival tissue obtained from the same set of patients. High-throughput screening of differentially expressed TRP channels in pterygium tissues was achieved with the help of Fluidigm 96.96 Dynamic Array Expression Chip and reactions were held in BioMark™ HD System Real-Time PCR platform. Statistically significant increases were found in the expression of 21 genes, mainly TRPA1 (p = 0.021), TRPC2 (p = 0.001), and TRPM8 (p = 0.003), in patients with PP, and in TRPC5 (p = 0.05), TRPM2 (p = 0.029), TRPM4 (p = 0.03), TRPM6 (p = 0.045), TRPM8 (p = 0.038), TRPV1 (p = 0.01) and TRPV4 (p = 0.025) genes in RP tissues. Collectively, TRP channel proteins appear to play pivotal roles in both the development and progression of pterygium, making them promising candidates for future therapeutic interventions in patients afflicted by this condition.

Canonical transient receptor potential channel 1 aggravates myocardial ischemia-and-reperfusion injury by upregulating reactive oxygen species

The canonical transient receptor potential channel (TRPC) proteins form Ca2+-permeable cation channels that are involved in various heart diseases. However, the roles of specific TRPC proteins in myocardial ischemia/reperfusion (I/R) injury remain poorly understood. We observed that TRPC1 and TRPC6 were highly expressed in the area at risk (AAR) in a coronary artery ligation induced I/R model. Trpc1−/− mice exhibited improved cardiac function, lower serum Troponin T and serum creatine kinase level, smaller infarct volume, less fibrotic scars, and fewer apoptotic cells after myocardial-I/R than wild-type or Trpc6−/− mice. Cardiomyocyte-specific knockdown of Trpc1 using adeno-associated virus 9 mitigated myocardial I/R injury. Furthermore, Trpc1 deficiency protected adult mouse ventricular myocytes (AMVMs) and HL-1 cells from death during hypoxia/reoxygenation (H/R) injury. RNA-sequencing-based transcriptome analysis revealed differential expression of genes related to reactive oxygen species (ROS) generation in Trpc1−/− cardiomyocytes. Among these genes, oxoglutarate dehydrogenase-like (Ogdhl) was markedly downregulated. Moreover, Trpc1 deficiency impaired the calcineurin (CaN)/nuclear factor-kappa B (NF-κB) signaling pathway in AMVMs. Suppression of this pathway inhibited Ogdhl upregulation and ROS generation in HL-1 cells under H/R conditions. Chromatin immunoprecipitation assays confirmed NF-κB binding to the Ogdhl promoter. The cardioprotective effect of Trpc1 deficiency was canceled out by overexpression of NF-κB and Ogdhl in cardiomyocytes. In conclusion, our findings reveal that TRPC1 is upregulated in the AAR following myocardial I/R, leading to increased Ca2+ influx into associated cardiomyocytes. Subsequently, this upregulates Ogdhl expression through the CaN/NF-κB signaling pathway, ultimately exacerbating ROS production and aggravating myocardial I/R injury.

Protective effect of ginsenoside Rg_1 aganist diabetic retinopathy by inhibiting NLRP3 inflammasome in type 2 diabetic mice

Ginsenoside Rg_1, one of the main active components of precious traditional Chinese medicine Ginseng Radix et Rhizoma, has the anti-oxidative stress, anti-inflammation, anti-aging, neuroprotection, and other pharmacological effects. Diabetic retinopathy(DR), the most common complication of diabetes, is also the main cause of impaired vision and blindness in the middle-aged and the elderly. The latest research shows that ginsenoside Rg_1 can protect patients against DR, but the protection and the mechanism are rarely studied. This study mainly explored the protective effect of ginsenoside Rg_1 against DR in type 2 diabetic mice and the mechanism. High fat diet(HFD) and streptozotocin(STZ) were used to induce type 2 diabetes in mice, and hematoxylin-eosin(HE) staining was employed to observe pathological changes in the retina of mice. The immunohistochemistry was applied to study the localization and expression of nucleotide-binding oligomerization domain-like receptors 3(NLRP3) and vascular endothelial growth factor(VEGF) in retina, and Western blot was used to detect the expression of nuclear factor-kappa B(NF-κB), p-NF-κB, NLRP3, caspase-1, interleukin-1β(IL-1β), transient receptor potential channel protein 6(TRPC6), nuclear factor of activated T-cell 2(NFAT2), and VEGF in retina. The results showed that ginsenoside Rg_1 significantly alleviated the pathological injury of retina in type 2 diabetic mice. Immunohistochemistry results demonstrated that ginsenoside Rg_1 significantly decreased the expression of NLRP3 and VEGF in retinal ganglion cells, middle plexiform layer, and outer plexiform layer in type 2 diabetic mice. According to the Western blot results, ginsenoside Rg_1 significantly lowered the expression of p-NF-κB, NLRP3, caspase-1, IL-1β, TRPC6, NFAT2, and VEGF in retina of type 2 diabetic mice. These findings suggest that ginsenoside Rg_1 can significantly alleviate DR in type 2 diabetic mice, which may be related to inhibition of NLRP3 inflammasome and VEGF. This study provides experimental evidence for the clinical application of ginsenoside Rg_1 in the treatment of DR.

Impact of Na+ permeation on collective migration of pulmonary arterial endothelial cells.

Collective migration of endothelial cells is important for wound healing and angiogenesis. During such migration, each constituent endothelial cell coordinates its magnitude and direction of migration with its neighbors while retaining intercellular adhesion. Ensuring coordination and cohesion involves a variety of intra- and inter-cellular signaling processes. However, the role of permeation of extracellular Na+ in collective cell migration remains unclear. Here, we examined the effect of Na+ permeation in collective migration of pulmonary artery endothelial cell (PAEC) monolayers triggered by either a scratch injury or a barrier removal over 24 hours. In the scratch assay, PAEC monolayers migrated in two approximately linear phases. In the first phase, wound closure started with fast speed which then rapidly reduced within 5 hours after scratching. In the second phase, wound closure maintained at slow and stable speed from 6 to 24 hours. In the absence of extracellular Na+, the wound closure distance was reduced by >50%. Fewer cells at the leading edge protruded prominent lamellipodia. Beside transient gaps, some sustained interendothelial gaps also formed and progressively increased in size over time, and some fused with adjacent gaps. In the absence of both Na+ and scratch injury, PAEC monolayer migrated even more slowly, and interendothelial gaps obviously increased in size towards the end. Pharmacological inhibition of the epithelial Na+ channel (ENaC) using amiloride reduced wound closure distance by 30%. Inhibition of both the ENaC and the Na+/Ca2+ exchanger (NCX) using benzamil further reduced wound closure distance in the second phase and caused accumulation of floating particles in the media. Surprisingly, pharmacological inhibition of the Ca2+ release-activated Ca2+ (CRAC) channel protein 1 (Orai1) using GSK-7975A, the transient receptor potential channel protein 1 and 4 (TRPC1/4) using Pico145, or both Orai1 and TRPC1/4 using combined GSK-7975A and Pico145 treatment did not affect wound closure distance dramatically. Nevertheless, the combined treatment appeared to cause accumulation of floating particles. Note that GSK-7975A also inhibits small inward Ca2+ currents via Orai2 and Orai3 channels, whereas Pico145 also blocks TRPC4, TRPC5, and TRPC1/5 channels. By contrast, gene silence of Orai1 by shRNAs led to a 25% reduction of wound closure in the first 6 hours but had no effect afterwards. However, in the absence of extracellular Na+ or cellular injury, Orai1 did not affect PAEC collective migration. Overall, the data reveal that Na+ permeation into cells contributes to PAEC monolayer collective migration by increasing lamellipodial formation, reducing accumulation of floating particles, and improving intercellular adhesion.

TRPV4 and TRPM8 as putative targets for chronic low back pain alleviation

The purpose of this study is to investigate the presence of nervous fibers and expression of TRP channels in samples harvested during decompressive/fusion spine surgeries from patients affected by chronic low back pain (CLBP). The aim was to understand if members of this family of receptors played a role in detection and processing of painful stimuli, to eventually define them as potential targets for CLBP alleviation. Expression of transient receptor potential (TRP) channels (A1, V1, V2, V4, and M8) was evaluated in samples from different periarticular sites of 6 patients affected by CLBP, at both protein and transcript levels. The capsular connective pathological tissue appeared infiltrated by sensitive unmyelinated nervous fibers. An increase in TRP channel mRNAs and proteins was observed in the pathological capsule compared with tissues collected from the non-symptomatic area in five of the six analyzed patients, independently by the location and number of affected sites. In particular, TRPV4 and TRPM8 were consistently upregulated in pathological tissues. Interestingly, the only patient showing a different pattern of expression also had a different clinical history. TRPV4 and TRPM8 channels may play a role in CLBP and warrant further investigations as possible therapeutic targets.

Role of TRP Channels in Shaping the Gut Microbiome.

Transient receptor potential (TRP) channel family proteins are sensors for pain, which sense a variety of thermal and noxious chemicals. Sensory neurons innervating the gut abundantly express TRPA1 and TRPV1 channels and are in close proximity of gut microbes. Emerging evidence indicates a bi-directional gut–brain cross-talk in several entero-neuronal pathologies; however, the direct evidence of TRP channels interacting with gut microbial populations is lacking. Herein, we examine whether and how the knockout (KO) of TRPA1 and TRPV1 channels individually or combined TRPA1/V1 double-knockout (dKO) impacts the gut microbiome in mice. We detect distinct microbiome clusters among the three KO mouse models versus wild-type (WT) mice. All three TRP-KO models have reduced microbial diversity, harbor higher abundance of Bacteroidetes, and a reduced proportion of Firmicutes. Specifically distinct arrays in the KO models are determined mainly by S24-7, Bacteroidaceae, Clostridiales, Prevotellaceae, Helicobacteriaceae, Rikenellaceae, and Ruminococcaceae. A1KO mice have lower Prevotella, Desulfovibrio, Bacteroides, Helicobacter and higher Rikenellaceae and Tenericutes; V1KO mice demonstrate higher Ruminococcaceae, Lachnospiraceae, Ruminococcus, Desulfovibrio and Mucispirillum; and A1V1dKO mice exhibit higher Bacteroidetes, Bacteroides and S24-7 and lower Firmicutes, Ruminococcaceae, Oscillospira, Lactobacillus and Sutterella abundance. Furthermore, the abundance of taxa involved in biosynthesis of lipids and primary and secondary bile acids is higher while that of fatty acid biosynthesis-associated taxa is lower in all KO groups. To our knowledge, this is the first study demonstrating distinct gut microbiome signatures in TRPA1, V1 and dKO models and should facilitate prospective studies exploring novel diagnostic/ therapeutic modalities regarding the pathophysiology of TRP channel proteins.

Differential regulation of TRP channel gene and protein expression by intervertebral disc degeneration and back pain

Intervertebral disc (IVD) degeneration and consequent low back pain (LBP) are common and costly pathological processes that require improved treatment strategies. Transient Receptor Potential (TRP) channels constitute a family of multimodal ion channels that have recently emerged as contributors to disc pathologies and were thus proposed as potential therapeutic targets, although limited data on their presence and function in the IVD exist. The purpose of this study was to determine the mRNA and protein expression of TRP channels in non-degenerated and degenerated human IVD tissue (with different pain intensity and chronicity) using gene array, conventional qPCR and immunohistochemistry. We could demonstrate that 26 out of 28 currently known TRP channels are expressed in the IVD on the mRNA level, thereby revealing novel therapeutic candidates from the TRPC, TRPM and TRPML subfamilies. TRPC6, TRPM2 and TRPML1 displayed enhanced gene and protein expression in degenerated IVDs as compared to non-degenerated IVDs. Additionally, the gene expression of TRPC6 and TRPML1 was influenced by the IVD degeneration grade. Pain intensity and/or chronicity influenced the gene and/or protein expression of TRPC6, TRPM2 and TRML1. Interestingly, decreased gene expression of TRPM2 was observed in patients treated with steroids. This study supports the importance of TRP channels in IVD homeostasis and pathology and their possible application as pharmacological targets for the treatment of IVD degeneration and LBP. However, the exact function and activation of the highlighted TRP channels will have to be determined in future studies.

Effect of Danggui Sini Decoction on the Behaviour and Dorsal Root Ganglion TRP Channel of Neuropathic Pain in CCI Rats

Danggui Sini decoction, a traditional Chinese medicine formula, has been extensively used as a remedy for neuropathic pain and other diseases in recent years. To explore whether Danggui Sini decoction can alleviate mechanical pain, thermal hyperalgesia, and cold pain at the same time, the role of temperature-sensitive transient receptor potential channel in neuropathic pain and the therapeutic effect of Danggui Sini decoction on neuropathic pain as well as the impact on the transient receptor potential pathway were explored in the present study. One hundred and twentyeight Sprague Dawley rats were separated randomly into 4 groups; the sham-operated group, chronic constriction injury of sciatic nerve model group, pregabalin group, and Danggui Sini decoction-treated group. The rats in the sham-operated group underwent surgery, but no nerve was ligated. The rest of the rats were subjected to sciatic nerve ligation. Rats in Danggui Sini decoction-treated group could be irrigated to Danggui Sini decoction. Rats in the sham-operated group and chronic constriction injury model group were gavaged with saline. Rats in pregabalin group were given pregabalin. Behavioral tests conducted were, acetone test and cold plate, hot plate experiment, and von Frey filaments on 4, 7, 14, 21st day, and then dorsal root ganglion neurons were take out. Nerve ligation from the ipsilateral L4-6 dorsal root ganglion were measured TRPM8, TRPA1, TRPV1, TRPV2, TRPV3, and TRPV4 proteins expression by immunofluorescence staining and Western-blot method. Danggui Sini decoction could significantly inhibit the cold allodynia and the mechanical allodynia. The immunofluorescence studies showed that the model group of dorsal root ganglia on TRPM8, TRPA1, TRPV1, TRPV2, TRPV3, and TRPV4 proteins were decreased. Western-blot results showed the the expression of TRPM8, TRPA1, TRPV1, TRPV2, TRPV3, and TRPV4 proteins in Danggui Sini decoction-treated group was reduced. Danggui Sini decoction could not only suppress the cold allodynia, but also alleviate mechanical allodynia and thermal hyperalgesia. Danggui Sini decoction could down-regulate abnormally high expression of temperature-dependent transient receptor potential channel protein.

Potential therapeutic value of transient receptor potential channels in male urogenital system.

Transient receptor potential (TRP) channels comprise a family of cation channels implicated in a variety of cellular processes including light, mechanical or chemical stimuli, temperature, pH, or osmolarity. TRP channel proteins are a diverse family of proteins that are expressed in many tissues. We debated our recent knowledge about the expression, function, and regulation of TRP channels in the different parts of the male urogenital system in health and disease. Emerging evidence suggests that dysfunction ofTRP channels significantly contributes to the pathophysiology of urogenital diseases. So far, there are many efforts underway to determine if these channels can be used as drug targets to reverse declines in male urogenital function. Furthermore, developing safe and efficacious TRP channel modulators is warranted for male urogenital disorders in a clinical setting.

The putative transient receptor potential channel protein encoded by the orf19.4805 gene is involved in cation sensitivity, antifungal tolerance, and filamentation in Candida albicans.

Transient receptor potential (TRP) channels, an ancient family of cation channels, are highly conserved in eukaryotes and play various physiological functions, ranging from sensation of ion homeostasis to reception of pain and vision. Calcium-permeable TRP channels have been identified from the plant Arabidopsis thaliana (AtCsc1) and the budding yeast Saccharomyces cerevisiae (ScCsc1). In this study, we characterized the functions of the Csc1 homolog, orf19.4805, in Candida albicans. Orf19.4805 is a protein of 866 amino acids and 11 transmembrane domains, which shares 49% identity (69% similarity) in amino acid sequence with ScRsn1. Here, we demonstrate that deletion of the orf19.4805 gene causes C. albicans cells to be sensitive to SDS (sodium dodecyl sulfate) and antifungal drugs, and tolerance to zinc, manganese, and cadmium ions. Candida albicans cells lacking orf19.4805 show a defect in filamentation in vitro. Therefore, orf19.4805 is involved in the regulation of cation homeostasis and filamentation in C. albicans.

Potential Treatment for Neuropsychiatry Disorders with TRPC5 Modulators

Patent Application Title: Quinazoline-2,4(1H,3H)-dione Derivatives as TRPC5 Modulators for the Treatment of Neuropsychiatry Disorders Patent Application Number: WO 2016/023826 Al Publication date: 18 February 2016 Priority Application: US 62/035,578 Priority date: 11 August 2014 Inventors: Chenard, B. L.; Gallaschun, R. J. Applicants: Hydra Biosciences, Inc.; 45 Moulton Street, Cambridge, MA, 02138, USA Boehringer Ingelheim International Gmbh; Binger Strasse 173, 55216 Ingelheim am Rhein (DE) Disease Area: Neuropsychiatry Disorders Biological Target: Short transient receptor potential channel 5 (TRPC5) Summary: The invention in this patent application relates to novel quinazoline-2,4(1H,3H)-dione derivatives. These compounds are TRPC5 modulators and may be used as medication for the treatment of conditions such as neuropsychiatric disorder, neurodegenerative disorder, nephropathy, and seizure disorder. Ion channel proteins mediate the ion flux across cellular membranes. Their proper expressions and functions are important for the maintenance of cell function as well as intracellular communications. Ion channels are important in modulating membrane potential and ion flux in cells. The misregulation of membrane potential and aberrant calcium handling are implicated in the pathogenesis of numerous diseases. Therefore, compounds that can either promote or inhibit particular ion channels are of great interest and may potentially provide therapy for different diseases. The short transient receptor potential channel 5 (TRPC5) is one of seven mammalian transient receptor potential channel proteins. TRPC5 is a multipass cation channel membrane protein that modulates the flux of calcium and sodium ions across cellular membranes. The influx of sodium and calcium leads to a depolarization of the cell, which in turn increases the probability that voltage-gated ion channels will reach the threshold required for activation. Thus, activation of nonselective cation channels can increase electrical excitability and the frequency of several voltage-dependent events including, but not limited to, neuronal action potentials, cardiac action potentials, smooth muscle contraction, cardiac muscle contraction, and skeletal muscle contraction. In addition, the activation of nonselective cation channels such as TRPC5 causes calcium influx and alters the intracellular free calcium concentrations. This has profound effects on signal transduction, gene expression, and cellular phenotype. Gene expression events include, but are not limited to, production of mRNAs encoding cell surface receptors, ion channels, and kinases. These changes in gene expression can lead to hyperexcitability in that cell. TRPC5 protein may form homomultimeric species such as a homo-TRPC5 tetramer, or it may form heteromultimeric structures with other transient receptor proteins such as TRPC1, TRPC3, and TRPC4. The term TRPC5 is used generically to include either polymeric form. Compounds that can modulate the function of TRPC5, such as the compounds described in this patent application, can maintain calcium homeostasis, modulate intracellular calcium levels, modulate membrane polarization, and potentially treat or prevent several diseases and disorders associated with calcium and/or sodium homeostasis or dys-homeostasis.

Retinal Dystrophy and Optic Nerve Pathology in the Mouse Model of Mucolipidosis IV

Mucolipidosis IV is a debilitating developmental lysosomal storage disorder characterized by severe neuromotor retardation and progressive loss of vision, leading to blindness by the second decade of life. Mucolipidosis IV is caused by loss-of-function mutations in the MCOLN1 gene, which encodes the transient receptor potential channel protein mucolipin-1. Ophthalmic pathology in patients includes corneal haze and progressive retinal and optic nerve atrophy. Herein, we report ocular pathology in Mcoln1(-/-) mouse, a good phenotypic model of the disease. Early, but non-progressive, thinning of the photoreceptor layer, reduced levels of rhodopsin, disrupted rod outer segments, and widespread accumulation of the typical storage inclusion bodies were the major histological findings in the Mcoln1(-/-) retina. Electroretinograms showed significantly decreased functional response (scotopic a- and b-wave amplitudes) in the Mcoln1(-/-) mice. At the ultrastructural level, we observed formation of axonal spheroids and decreased density of axons in the optic nerve of the aged (6-month-old) Mcoln1(-/-) mice, which indicates progressive axonal degeneration. Our data suggest that mucolipin-1 plays a role in postnatal development of photoreceptors and provides a set of outcome measures that can be used for ocular therapy development for mucolipidosis IV.

Role of TRP channels in the cardiovascular system.

The transient receptor potential (TRP) superfamily consists of a large number of nonselective cation channels with variable degree of Ca(2+)-permeability. The 28 mammalian TRP channel proteins can be grouped into six subfamilies: canonical, vanilloid, melastatin, ankyrin, polycystic, and mucolipin TRPs. The majority of these TRP channels are expressed in different cell types including both excitable and nonexcitable cells of the cardiovascular system. Unlike voltage-gated ion channels, TRP channels do not have a typical voltage sensor, but instead can sense a variety of other stimuli including pressure, shear stress, mechanical stretch, oxidative stress, lipid environment alterations, hypertrophic signals, and inflammation products. By integrating multiple stimuli and transducing their activity to downstream cellular signal pathways via Ca(2+) entry and/or membrane depolarization, TRP channels play an essential role in regulating fundamental cell functions such as contraction, relaxation, proliferation, differentiation, and cell death. With the use of targeted deletion and transgenic mouse models, recent studies have revealed that TRP channels are involved in numerous cellular functions and play an important role in the pathophysiology of many diseases in the cardiovascular system. Moreover, several TRP channels are involved in inherited diseases of the cardiovascular system. This review presents an overview of current knowledge concerning the physiological functions of TRP channels in the cardiovascular system and their contributions to cardiovascular diseases. Ultimately, TRP channels may become potential therapeutic targets for cardiovascular diseases.

P3-4-4 - Investigation of the Relationship Between Breast Cancer and Transient Receptor Potential (Trp) Genes

Background: Breast cancer is the most common cancer type among woman. Ion channels are important for different physiologic functions as muscle contraction and hormone secretion. Recently the effect of Transient Receptor Potential (TRP) channels on calcium balance, cell proliferation, cell differantiation, tumor invasion, oncogen regulation and resistance to apoptotic cell death has been demonstrated. Some members of TRP family as TRPV6, TRPM1, TRPM8 and TRPM5 has been directly associated with cancer. The aim of this study is to determine the importance of TRP channels in breast cancer.Methods: Thirty two breast cancer patients were enrolled. Normal breast tissue and breast cancer tissue has been taken from each patient during operation. Tissues has been protected in liquid nitrogen. RNA isolation from tissues was made with RNA isolation kit and cDNA has been derived with reverse transcriptase reaction (PCR) from RNA. Expression of 20 genes containing TRPC, TRPM, TRPV and TRPA genes has been investigated with Biomark Fludigm nano Real Time PCR tool.Results: The expression of TRPM1, TRPC7 and TRPC5 genes has not been observed in normal breast and breast cancer tissues. Compared to normal breast tissue TRPMA1, TRMPV5, TRPM5 and TRPV6 genes expression was at high levels in breast cancer tissues. There was no expression of TRPMA1, TRMPV5, TRPM5 and TRPV6 genes in normal breast tissues.Conclusion: In this study the importance of TRP channels in breast cancer has been evaluated. Expression of genes for regulating the TRP channel proteins could be an important candidate for breast cancer diagnosis and treatment. Especially expression of TRPMA1, TRMPV5, TRPM5 and TRPV6 genes has been determined at high levels in breast cancer tissues. Evaluation of the clinical effects of these genes on breast cancer progression can be used at new researchs for diagnosis and treatment options of breast cancer.

Functional biology of ion channels: a review

Over the past few decades, a great deal of attention has been focused on discovering the protein partners that form mechano- electrical transduction (MeT) channels in somatic mechanoreceptors. Two classes of ion channel proteins are leading candidates: amiloride-sensitive channel (ASCs) and transient receptor potential (TRP) channel proteins. Here, we surveyed the literature to establish that most, if not all mechanoreceptor neurons in mice express multiple ASC and TRP channel proteins. But, the landscape of ion channel co-expression in mechanoreceptor neurons is only beginning to be mapped. Future work aimed at refining such maps for mammalian mechanoreceptor neurons will be critical for deeper understanding. Also, each of these potential MeT channel subunits operates within a large company of other ion channel actors that increase the complexity, flexibility, and robustness of somatosensory neuron function. Recently, two additional classes of membrane proteins (Piezo and TMC) have been linked to mechano-transduction. This situation is likely to exist in other mechanoreceptor neurons, including those responsible for touch and pain sensation in mammals.

Quantitative neuroimaging in mucolipidosis type IV

Mucolipidosis type IV (MLIV) is an autosomal recessive disorder resulting from mutations in the MCOLN1 gene. This gene encodes the endosomal/lysosomal transient receptor potential channel protein mucolipin-1 (TRPML1). Affected patients suffer from neurodevelopmental abnormalities and progressive retinal dystrophy. In a prospective natural history study we hypothesized the presence of an additional slow cerebral neurodegenerative process. We have recruited 5 patients, tested their neurodevelopmental status, and measured cerebral regional volumes and white matter integrity using MRI yearly. Over a period of up to 3years, MLIV patients remained neurologically stable. There was a trend for increased cortical and subcortical gray matter volumes and increased ventricular size, while white matter and cerebellar volumes decreased. Mean diffusivity (MD) was increased and fractional anisotropy (FA) values were below normal in all analyzed brain regions. There was a positive correlation between motor scores of the Vineland Scale and the FA values in the corticospinal tract (corr coef 0.39), and a negative correlation with the MD values (corr coef −0.50) in the same brain region. We conclude from these initial findings that deficiency in mucolipin-1 affects the entire brain but that there might be a selective regional cerebral neurodegenerative process in MLIV. In addition, these data suggest that diffusion-weighted imaging might be a good biomarker for following patients with MLIV. Therefore, our findings may be helpful for designing future clinical trials.

Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity

BackgroundThe mechanism underlying respiratory virus-induced cough hypersensitivity is unknown. Upregulation of airway neuronal receptors responsible for sensing physical and chemical stimuli is one possibility, and the transient receptor potential (TRP)...

Systematic Screens for Proteins That Interact with the Mucolipidosis Type IV Protein TRPML1

Mucolipidosis type IV is a lysosomal storage disorder resulting from mutations in the MCOLN1 gene, which encodes the endosomal/lysosomal Transient Receptor Potential channel protein mucolipin-1/TRPML1. Cells isolated from Mucolipidosis type IV patients and grown in vitro and in in vivo models of this disease both show several lysosome-associated defects. However, it is still unclear how TRPML1 regulates the transport steps implicated by these defects. Identifying proteins that associate with TRPML1 will facilitate the elucidation of its cellular and biochemical functions. We report here two saturation screens for proteins that interact with TRPML1: one that is based on immunoprecipitation/mass spectrometry and the other using a genetic yeast two-hybrid approach. From these screens, we identified largely non-overlapping proteins, which represent potential TRPML1-interactors., Using additional interaction assays on some of the potential interactors from each screen, we validated some proteins as candidate TRPML1 interactors In addition, our analysis indicates that each of the two screens not only identified some false-positive interactors, as expected from any screen, but also failed to uncover potential TRPML1 interactors. Future studies on the true interactors, first identified in these screens, will help elucidate the structure and function of protein complexes containing TRPML1.

Revealing the Underlying Mechanism of Ischemia Reperfusion Injury Using Bioinformatics Approach

Background/Aims: To reveal the potential pathogenesis of ischemia/reperfusion (I/R) injury. Methods: GSE9943 were downloaded from Genome Expression Omnibus database, including I/R and control samples for both Brown Norway (BN) and Sprague Dawley (SD) rats (3 rats/each group). Then differentially expressed genes (DEGs) were identified by limma package. miRNA-target gene network pairs were predicted using WebGestalt, and protein-protein interactions (PPI) were identified based on STRING database, followed by the networks construction using Cytoscape. Next, ClusterONE was used for modules screening. Furthermore, functional analyses were performed to common DEGs and genes. Results: Totally, 23 common DEGs of BR and SD rats were screened, enriched in functions, such as regulation of cellular protein metabolic process, response to wounding, proteinaceous extracellular matrix, and Enzyme inhibitor activity. MIR-29A, MIR-29B and MIR-29C were discovered both in up- and down-regulated miRNA-target gene networks. Genes in the PPI network were significantly disturbed in p53 signaling, complement and coagulation cascades pathway. Four modules were found significantly disturbed cytochrome P450, Serine/threonine protein kinase, calcium binding and Transient receptor potential channel protein domains. Conclusion: During I/R injury, many genes mutated, interrupting several biological functions, pathways and protein domains. MIR-29C and TRPC6 were suggested to be potential novel targets for this disease.