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Transient Receptor Potential Channels and Itch
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Mahar Fatima, Jingyi Liu, Bo Duan
Selective serotonin reuptake inhibitors (SSRIs) that are widely used to treat depressive disorders have been commonly associated with adverse side effects including skin rashes and urticaria (hives), and itch. SSRI sertraline-, citalopram-, and fluoxetine-elicited scratching in the mouse cheek model of acute itch was revoked in rodents that were co-administered TRPC4 antagonist ML204. Sertraline-evoked itch is diminished in Trpc4 knockout mice (109). SSRI or serotonin binds and activates serotonin receptor 2B, a GPCR that is coupled Gq/G11 leading to the activation of phospholipase C β3 which mediates the opening of the TRPC4 channel (109) (Figure 16.1). Another TRPC channel, TRPC3, is highly enriched in non-peptidergic MrgprD+ sensory neurons but does not play any role in MrgprD evoked chemical itch behaviors (110).
Vascular smooth muscle: excitation, contraction and relaxation
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
ROCs are cation-conducting channels that are about three- to fivefold more permeable to Ca2+ than Na+. A lag of ~0.1-1.0 s between agonist application and channel activation indicates that a relatively slow, biochemical pathway leads to channel activation (Figure 12.6a). When an agonist binds to its G-protein-coupled receptor, for example, noradrenaline to the a1 adrenergic receptor, the activated receptor splits trimeric Gq protein into Gqa and Gqpy components, and the former activates the membrane-bound enzyme phospholipase Cp (PLCp). PLCp catalyses the breakdown of a membrane lipid, phosphatidylinositol 4,5-bisphosphate (PIP2), into cytosolic IP3 and lipophilic DAG (Figure 12.6b). DAG activates the ROCs directly, leading to extracellular Ca2+ influx and VSM contraction. Available evidence supports the involvement of short TRP channels 3, 6 and 7 (TRPC3, TRPC6 and TRPC7) as VSM ROCs, but as TRPs can form heteromultimeric channels this is almost certainly a simplified view. It also seems that IP3, like DAG, may activate TRPs directly (independently of Ca2+), certainly in the case of TRPC3. Note that the ‘phar- macomechanical’ contraction due to ROCs does not require an initial membrane depolarization, although the ROC- conducted current can cause a small, incidental depolarization (Figure 12.2c). Depolarization-independent contraction is typical of large arteries. It also appears that TRPC3 displays constitutive activity, which provides a low, background permeability in unstimulated vessels, resulting from background levels of DAG. The consequent small, inward cation current contributes to the resting potential in some arteries, and can be enhanced by vasoconstrictor agonists like noradrenaline to increase VDCC open probability.
Research progress in the mechanism of calcium ion on contraction and relaxation of airway smooth muscle cells
Published in Journal of Receptors and Signal Transduction, 2021
Xiyu Du, Juan Zhi, Dong Yang, Qianyu Wang, Xiang Luo, Xiaoming Deng
A recently report show a new pathway in the context of calcium regulation is calmodulin/NFAT [11,14]. Recent studies have reported that calcineurin can regulate local calcium signal and contractility in ASM through RyR channel [15]. On the contrary, the local Ca2+ signal produced by TRPV4 can activate calcineurin to further increase the Ca2+ in ASM and promote the proliferation of ASMc. In addition, Ca2+ influx channel TRPC3 can activate calmodulin/NFAT pathway to regulate airway contractility. In addition to Ca2+, calcineurin is also involved in the regulation of actin polymerization and tension in ASM. Therefore, understanding the related mechanism of calmodulin can guide its specific application in a variety of airway-related diseases.
Electrolyte handling in the isolated perfused rat kidney: demonstration of vasopressin V2-receptor-dependent calcium reabsorption
Published in Upsala Journal of Medical Sciences, 2020
Krister Bamberg, Lena William-Olsson, Ulrika Johansson, Anders Arner, Judith Hartleib-Geschwindner, Johan Sällström
The mechanisms for AVP-mediated calcium reabsorption are not clear. Data on PTH-mediated transepithelial calcium transport have been linked to the apical transient receptor potential cation channel subfamily V member 5 and 6 (TRPV5/6) in the distal convoluted tubule and the connecting tubule (25). In the collecting duct, further downstream of the tubular system, canonical transient receptor potential channel member 3 (TRPC3) may instead have a particular role for calcium reabsorption (26). Interestingly, AVP has been shown to induce co-localization of AQP2 channels and TRPC3 cation channels to the apical cell membrane in the medullary collecting duct. Overexpression of these channels in cultured collecting duct cells was also related to increased transepithelial calcium flux (27). Accordingly, calcium channels stimulated by AVP may, besides being involved in the signalling mechanisms for aquaporin trafficking, directly contribute to calcium reabsorption. In line with this, TRPC3 knockout mice displayed an increased urinary calcium concentration compared to their wild-type controls when subjected to water deprivation (28). The correlation observed in the present study between change in osmolality and urine flow and change in calcium reabsorption (Figure 3), as well as their temporal relationship (Figure 2), consequently further supports that AVP increases reabsorption of both water and calcium through incorporation of these channels on the apical membrane of the cells in the collecting duct. The physiological relevance may be to protect against urolithiasis during water restriction, where otherwise calcium levels could be elevated to levels risking precipitation. Another indication on the possible role of this channel in pathophysiology comes from a case report where TRPC3 expression was found to be upregulated in a patient with Williams–Beuren syndrome, a rare neurodevelopmental disorder also associated with hypercalcemia (29). However, TRPC3 expression was found both in the kidney and the intestinal epithelium. Thus, an increased intestinal uptake could also have contributed to the elevated plasma calcium concentrations.