Roles of Epithelial and Mesenchymal TRP Channels in Mediating Inflammatory Fibrosis

The maintenance of normal vision is dependent on preserving corneal transparency. For this to occur, this tissue must remain avascular and its stromal architecture needs to be retained. Epithelial transparency is maintained provided the uppermost stratified layers of this tissue are composed of terminally differentiated non-keratinizing cells. In addition, it is essential that the underlying stromal connective tissue remains avascular and scar-free. Keratocytes are the source of fibroblasts that are interspersed within the collagenous framework and the extracellular matrix. In addition, there are sensory nerve fibers whose lineage is possibly either neural crest or mesenchymal. Corneal wound healing studies have been undertaken to delineate the underlying pathogenic responses that result in the development of opacification following chemical injury. An alkali burn is one type of injury that can result in severe and long- lasting losses in ocular transparency. During the subsequent wound healing process, numerous different proinflammatory cytokines and proteolytic enzymes undergo upregulation. Such increases in their expression levels induce maladaptive expression of sustained stromal inflammatory fibrosis, neovascularization, and losses in the smooth optical properties of the corneal outer surface. It is becoming apparent that different transient receptor potential channel (TRP) isoforms are important players in mediating these different events underlying the wound healing process since injury upregulates both their expression levels and functional involvement. In this review, we focus on the involvement of TRPV1, TRPA1 and TRPV4 in mediating some of the responses that underlie the control of anterior ocular tissue homeostasis under normal and pathological conditions. They are expressed on both different cell types throughout this tissue and also on corneal sensory nerve endings. Their roles have been extensively studied as sensors and transducers of environmental stimuli resulting from exposure to intrinsic modulators and extrinsic ligands. These triggers include alteration of the ambient temperature and mechanical stress, etc., that can induce pathophysiological responses underlying losses in tissue transparency activated by wound healing in mice losses in tissue transparency. In this article, experimental findings are reviewed about the role of injury-induced TRP channel activation in mediating inflammatory fibrotic responses during wound healing in mice.

Design Maps of TRPM8 as a Thermometer for Cold Detection

The menthol sensor TRPM8 can be activated by cold and thus serves as a thermometer in a primary afferent sensory neuron for noxious cold detection. However, the underlying design principle is unknown. Here, a hairpin topological structural model and graph theory were prepared to test a role of the cold-dependent hairpin formation in the cold-evoked gating pathway of TRPM8. The results showed that the formation of a large lipid-dependent hairpin initiates a low temperature threshold in favor of TRPM8 activation. Furthermore, two smaller hairpins, which enhance the coupled interactions of the voltage-sensor-like domain with both the pore domain and the TRP domain, can stabilize the cold efficacy and work as a fuse to prevent cold denaturation. The cold-induced hairpin rearrangements along the gating pathway may be necessary for the high cold sensitivity. This hairpin model may provide a structural basis for activation of the thermo-gated TRP channels at low temperature.

Influence of Cold-TRP Receptors on Cold-Influenced Behaviour

The transient receptor potential (TRP) channels, TRPA1 and TRPM8, are thermo-receptors that detect cold and cool temperatures and play pivotal roles in mediating the cold-induced vascular response. In this study, we investigated the role of TRPA1 and TRPM8 in the thermoregulatory behavioural responses to environmental cold exposure by measuring core body temperature and locomotor activity using a telemetry device that was surgically implanted in mice. The core body temperature of mice that were cooled at 4 °C over 3 h was increased and this was accompanied by an increase in UCP-1 and TRPM8 level as detected by Western blot. We then established an effective route, by which the TRP antagonists could be administered orally with palatable food. This avoids the physical restraint of mice, which is crucial as that could influence the behavioural results. Using selective pharmacological antagonists A967079 and AMTB for TRPA1 and TRPM8 receptors, respectively, we show that TRPM8, but not TRPA1, plays a direct role in thermoregulation response to whole body cold exposure in the mouse. Additionally, we provide evidence of increased TRPM8 levels after cold exposure which could be a protective response to increase core body temperature to counter cold.

TRP channel expression correlates with the epithelial–mesenchymal transition and high-risk endometrial carcinoma

Transient receptor potential (TRP) channels excel in cellular sensing as they allow rapid ion influx across the plasma membrane in response to a variety of extracellular cues. Recently, a distinct TRP mRNA expression signature was observed in stromal cells (ESC) and epithelial cells (EEC) of the endometrium, a tissue in which cell phenotypic plasticity is essential for normal functioning. However, it is unknown whether TRP channel mRNA expression is subject to the phenotypic switching that occurs during epithelial to mesenchymal transition (EMT) and mesenchymal to epithelial transition (MET), and whether TRP channel mRNA expression is associated with aggressive phenotypes in endometrial cancer (EC). Here, we induced EMT and MET in vitro using in primary EEC and ESC, respectively, and analyzed expression and functionality of TRP channels using RT-qPCR and intracellular Ca2+ imaging. The outcome of these experiments showed a strong association between TRPV2 and TRPC1 mRNA expression and the mesenchymal phenotype, whereas TRPM4 mRNA expression correlated with the epithelial phenotype. In line herewith, increased TRPV2 and TRPC1 mRNA expression levels were observed in both primary and metastatic EC biopsies and in primary EC cells with a high EMT status, indicating an association with an aggressive tumor phenotype. Remarkably, TRPV2 mRNA expression in primary EC biopsies was associated with tumor invasiveness and cancer stage. In contrast, increased TRPM4 mRNA expression was observed in EC biopsies with a low EMT status and less aggressive tumor phenotypes. Taken together, this dataset proved for the first time that TRP channel mRNA expression is strongly linked to cellular phenotypes of the endometrium, and that phenotypic transitions caused by either experimental manipulation or malignancy could alter this expression in a predictable manner. These results implicate that TRP channels are viable biomarkers to identify high-risk EC, and potential targets for EC treatment.

TRP Channels as Molecular Targets to Relieve Cancer Pain

Transient receptor potential (TRP) channels are critical receptors in the transduction of nociceptive stimuli. The microenvironment of diverse types of cancer releases substances, including growth factors, neurotransmitters, and inflammatory mediators, which modulate the activity of TRPs through the regulation of intracellular signaling pathways. The modulation of TRP channels is associated with the peripheral sensitization observed in patients with cancer, which results in mild noxious sensory stimuli being perceived as hyperalgesia and allodynia. Secondary metabolites derived from plant extracts can induce the activation, blocking, and desensitization of TRP channels. Thus, these compounds could act as potential therapeutic agents, as their antinociceptive properties could be beneficial in relieving cancer-derived pain. In this review, we will summarize the role of TRPV1 and TRPA1 in pain associated with cancer and discuss molecules that have been reported to modulate these channels, focusing particularly on the mechanisms of channel activation associated with molecules released in the tumor microenvironment.

Effectiveness of Mouth Rinsing versus Ingesting Pickle Juice for Alleviating Electrically Induced Cramp in Physically Active Adults

(1) Background: Stimulating oropharyngeal transient receptor potential (TRP) channels inhibits muscle cramping by triggering a supraspinal reflex to reduce α-motor neuron hyperexcitability. This study investigated whether the longer stimulation of the TRP channels via mouth rinsing with PJ is more effective than drinking PJ at inhibiting an electrically induced muscle cramp (EIMC). Both conditions were compared to the control (water). (2) Methods: The tibial nerves in 11 cramp-prone adults were percutaneously stimulated to elicit an EIMC of the flexor hallucis brevis in three trials that took place one week apart from each other. At cramp onset, the participants received mouth rinsing and expelling PJ (25 mL), ingesting PJ (1 mL∙kg−1 body-mass (BM)), or ingesting water (1 mL∙kg−1 BM). Cramp onset and offset were induced by electromyography, and the severity of discomfort was recorded using a visual analogue scale (VAS). (3) Results: The median time to cramp cessation as a percentage of water was 82.8 ± 14.63% and 68.6 ± 47.78% for PJ ingestion and PJ mouth rinsing, respectively. These results had large variability, and no statistically significant differences were observed. There were also no differences in perceived cramp discomfort between conditions, despite the hazard ratios for the time taken to reach VAS = 0, which was higher than water (control) for PJ ingestion (22%) and mouth rinsing (35%) (p = 0.66 and 0.51, respectively). (4) Conclusions: The data suggest no difference in cramp duration and perceived discomfort between PJ and water.

The science of “smell” and the noble for “hugs:” making “sense?”

David Julius and Ardem Patapoutian were jointly awarded the 2021 Nobel Prize in Physiology and Medicine for their discoveries of receptors for temperature and touch. It was a phenomenal moment for the scientific community, more for the discovery that forms the basic fabric of our everyday life—ever imagined how life would have been without feeling the aroma around? Or even the dangers of accidentally touching a heated object. Dr Julius and Dr Patapoutian, independently discovered key mechanisms of how living organisms sense heat, cold, and touch. The journey started when Dr Julius, at the University of California, San Francisco, used a key ingredient in hot chili peppers to identify a protein in nerve cells that respond to these stimuli. Using capsaicin, the pungent component of chili peppers, he provided fundamental insights into mechanisms of pain. Then using a meticulous cDNA library-based functional screening from sensory neurons to search for the gene(s) that could confer capsaicin sensitivity, Dr Julius identified for the first time a novel ion channel (now called transient receptor potential [TRP] vanilloid 1) belonging to the family of TRP ion channels associated with the pain sensitivity. A painful exercise indeed! While Prof Julius was exploring the oceans and skies to hunt for sensory pain pathways, quite independently, Dr Patapoutian of Scripps Research Institute La Jolla, California, was searching for a similar thing that seemed to bother him equally. How do we sense touches? After all, there are so many emotions packaged in this small five-letter word, touch. The mother’s touch is the first sensation that every single of us always cherishes. Dr Patapoutian research is centered around finding candidate genes in a mechanosensitive cell line that could respond to mechanical stimuli. After a thorough search, the team identified two mechanically-activated ion channels, PIEZO1 and PIEZO2, representing an entirely novel class of mechanical sensors-based ion channels. What is fascinating is the idea that discovery of the smell and touch receptor stretches far beyond just touch and temperature sensations only. Mutations in other TRP channels are involved in neurodegenerative disorders and skeletal dysplasia, while mutations in PIEZO channels help control critical functions such as respiration and blood pressure regulation. So now, the mysterious world surrounding us looks more transparent and clearer. The molecular landscape is defined with precision. We now have a chemical entity behind all these emotions and intuition. The warm hug that makes our day is now millions of ions crisscrossing the ion channels. There is a different side to this too. How will the world look if everything is defined as a chemical entity? Won’t we lose the charm? After all, so much within the subtleness remains charmful when wrapped within the veil of ignorance. Knowing too much about something steals the show.