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Eukaryotic Mechanosensitive Ion Channels
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Various transient receptor potential (TRP) channels are involved in mechanosensation in sensory neurons, including TRPV1, TRPC5, and TRPV4. TRPV1 has recently been implicated in controlling the stretch response of bladder urothelium, since the knock-out mice showed defects in voiding. However, no mechano-currents have been recorded from urothelial cells, suggesting that TRPV1 may detect the presence of molecules produced by stretch and may act downstream of the real MA channel [7]. TRPC5 has been shown opened by hypo‐osmolality and plays a role in baroreceptor mechanosensing [8]. However, since a hypo-osmotic stimulus contains both chemical (decreased ionic strength) and mechanical (cell swell) components, more specific mechanical activation should be taken into consideration. A recent study provides clear evidence that membrane stretch failed to activate TRPC5 in a heterologous expression system [9]. These studies suggest that both TRPV1 and TRPC5 serve the downstream of mechanosensation as MS channels.
Basic Thermal Physiology: What Processes Lead to the Temperature Distribution on the Skin Surface
Published in Kurt Ammer, Francis Ring, The Thermal Human Body, 2019
TRPV4, originally identified as an osmo-sensory ion channel, is also activated by temperatures between 27°C and 42°C. Phorbol esters and low osmolarity lead to expression of TRPV4, which was identified in the kidney, liver, trachea, heart, skin, fat, peripheral and central nervous system including the inner ear, hypothalamus and brain.
Inflammatory Responses Acquired Following Environmental Exposures Are Involved in Pathogenesis of Musculoskeletal Pain
Published in Kohlstadt Ingrid, Cintron Kenneth, Metabolic Therapies in Orthopedics, Second Edition, 2018
Ritchie C. Shoemaker, James C. Ryan
Guilak and Liedtke [96] in 2010 suggests that TRPV4 is the “sixth sense,” as it is activated by heat, cold, mechanical loading, osmolality, physical and chemical stimuli. TRPV4 is particularly relevant to musculoskeletal systems as it is expressed in articular cartilage and bone, reacting to osmotic stress. This paper suggests that TRPV4 exerts a regulatory role for a sensory channel in musculoskeletal tissues. Disruption of regulation by biotoxins is a recurrent theme in biotoxin medicine.
Investigational drugs in early phase clinical trials targeting thermotransient receptor potential (thermoTRP) channels
Published in Expert Opinion on Investigational Drugs, 2020
Asia Fernández-Carvajal, Rosario González-Muñiz, Gregorio Fernández-Ballester, Antonio Ferrer-Montiel
TRPV4 is broadly expressed in DRG, TG, and nodose ganglion (NG) neurons, bladder urothelium, kidney epithelium, vascular endothelium, inner ear, pulmonary aortic smooth muscle, skeletal muscle fibers, cardiac fibroblasts, pancreatic islets, myocytes, keratinocytes, adipocytes, and chondrocytes [49]. Due to its wide expression profile, TRPV4 is implicated in multiple pathophysiological states. TRPV4 sensitization by inflammation-triggered intracellular signaling leads to pain behavior in mice to hypo-osmotic and mechanical stimuli. In the vasculature system, TRPV4 is a regulator of vessel tone and is implicated in hypertension in diabetes due to endothelial dysfunction. TRPV4 is a negative regulator of epithelial and endothelial barrier function, as its function can disrupt these critical protective barriers [50]. In respiratory function, TRPV4 is involved in cystic fibrosis, ciliary beat frequency, bronchoconstriction, chronic obstructive pulmonary disease, pulmonary hypertension, acute respiratory distress syndrome, and cough [51]. Furthermore, a high number of mutations have been found in the TRPV4 gene compared to the other members of the TRP superfamily, that are causative for several human diseases, which affect the skeletal and the peripheral nervous systems, with highly variable phenotypes [46].
Exploring the ‘cold/hot’ properties of traditional Chinese medicine by cell temperature measurement
Published in Pharmaceutical Biology, 2020
Suyun Yu, Can Li, Yushi Ding, Shuai Huang, Wei Wang, Yuanyuan Wu, Fangxu Wang, Aiyun Wang, Yuexia Han, Zhiguang Sun, Yin Lu, Ning Gu
As an important member of temperature sensitive receptors, TRPV4 has a certain level of basal activation at room temperatures and is widely distributed in various organs. We then screened cells with a high expression level of TRPV4 through CCLE analysis and experimental verification. The CCLE database includes genetic information on more than 1000 cell lines and has been visualized, including copy number, mRNA expression (Affy, RNAseq), and so on (Barretina et al. 2012, 2019). It allows us to perform a predictive analysis of the gene expression of cells in silicon. The analysis manifested that melanoma cell lines showed a high expression level of TRPV4, of which A375 was the highest in experimental verification. To verify the relationship between TRPV4 and cell heat production, we used the agonist and antagonist of TRPV4 to conduct a preliminary study. GSK1016790A, as a specific agonist of TRPV4, can induce calcium influx. Eventually, the temperature of A375 cells was raised and maintained at a certain level. By contrast, when the TRPV4 was inhibited by HC067047, the temperature of the cells showed a downward trend and remained unchanged during the experiment. Mammals could sense hot and cold through TRP channels, despite that the mechanism remains unclear. Combined with our experimental results, it is speculated that TRPV4 may cause changes in intracellular calcium concentration through the opening/closing of its channels, thus eventually alter the heat production in cells. Among which, energy metabolism perhaps plays an important role in the heat production of cells.
TRPV4 activation in rat carotid artery in DOCA hypertension involves eNOS and endothelium-derived contractile factor (EDCF)
Published in Clinical and Experimental Hypertension, 2019
J R Dash, S K Mishra, S Parida, T U Singh, S Choudhury, K Muniyappa
In conclusion, we have used pharmacological methods in isolated tissue in control, UNX, and DOCA-treated hypertensive rats to evaluate the role of TRPV4 in vasoregulation of carotid artery in hypertension. It was observed that GSK1016790A (GSK)-induced relaxation of rat carotid artery was potently attenuated in DOCA-treated hypertensive rats which indicate that TRPV4 may regulate the vascular tone of the carotid artery in DOCA hypertension in rat because GSK1016790A (GSK) is a selective TRPV4 agonist. This attenuated response to GSK in DOCA-treated hypertensive rats was potentiated by blockade of cyclooxygenase by Indomethacin. Thus, some cyclooxygenase-derived vasoconstrictors may be involved in the attenuated response to GSK in DOCA-treated hypertensive rats. By blockade of nitric oxide synthase by eNOS inhibitor L-NAME, the attenuated response to GSK in DOCA-treated hypertensive rats was abolished, and a contractile pathway was expressed which was sensitive to indomethacin. Therefore, we hypothesize that TRPV4 may regulate the vascular tone of rat carotid artery through an attenuated NO pathway and stimulation of the release of contractile prostanoids in the DOCA hypertensive rats. Hence, the role of TRPV4 modulation in hypertension may be a very important target for the therapeutic approach. Investigation of the role of endothelial TRP channels in regulation of vascular tone is still at an early stage, and many questions remain to be answered.