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Ion Channels in Human Pluripotent Stem Cells and Their Neural Derivatives
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Ritika Raghavan, Robert Juniewicz, Maharaib Syed, Michael Lin, Peng Jiang
Cortical excitatory neurons can be generated through differentiation from hPSCs following fundamental developmental principles (10,11), accelerated differentiation, and the direct reprogramming method (22,23,43). Through patch-clamp recordings, ion channel properties have been examined in human excitatory neurons. These ion channels include the KV and NaV channels, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and TRPC channels. The human excitatory neurons exhibit gradual maturation along with the culture time as indicated by the hyperpolarized resting membrane potential (−70 mV) while also increasing the amplitude and decreasing the duration of action potentials (43). Neurons differentiated from hPSCs also developed synapses and exhibited synaptic activities (44). The development of functional synapses can also be accelerated by co-culture with astrocytes (45). Activation of TRPC produces calcium transients, which play a key role in governing many neurodevelopmental processes such as proliferation, migration, and neurite growth (46–48). The TRPC1 and TRPC4 ion channels were shown to be expressed in hPSC-derived excitatory neurons through q-PCR. Using calcium imaging, it was also observed that calcium transients decreased significantly upon the application of TRPC antagonist: SKF96365. Furthermore, TRPC channel inhibition resulted in reduction of neurite outgrowth and neurite extension (42).
Endothelium
Published in Neil Herring, David J. Paterson, Levick's Introduction to Cardiovascular Physiology, 2018
Neil Herring, David J. Paterson
Store-operated channels (SOCs) are again Ca2+- conducting channels in the surface membrane, but their activation is associated with Ca2+ store release. Endothelial SOCs may be TRP channels since TRPC1 is found in human endothelium. Furthermore, a role for TRPC4 and TRPC6, and possibly heteromeric channel complexes of these proteins, have also been suggested to underlie SOC Ca2+ entry (Figure 9.7). However, this remains a controversial area, to the extent that an involvement of TRPs as SOCs in native endothelium has been questioned. Of note, much of the experimental work in the area has studied cultured endothelial cells, conditions known to increase TRP protein expression. A second type of SOC is composed of Orai proteins. This channel is exquisitely Ca2+-selective, and is activated by an endoplasmic reticulum protein, stromal interaction molecule 1, following Ca2+ store release; so, it is also called the Ca2+-release activated Ca2+ (CR AC) channel. SOC activation leads to an influx of extracellular Ca2+, called either capacitive or store-operated Ca2+ entry. This raises the free Ca2+ level, as well as restocking the sarcoplasmic reticulum store. SOCs are thought to be more abundant than ROCs in many types of endothelium.
Screening of rosmarinic acid from Salvia miltiorrhizae acting on the novel target TRPC1 based on the ‘homology modelling–virtual screening–molecular docking–affinity assay–activity evaluation’ method
Published in Pharmaceutical Biology, 2023
Wei Quan, Yuan Wang, Yu-han Chen, Qing Shao, Yang-ze Gong, Jie-wen Hu, Wei-hai Liu, Zi-jun Wu, Jie Wang, Shan-bo Ma, Xiao-qiang Li
Swiss-Model was searched for the best template of TRPC1. It was found that the sequence of short transient receptor potential channel 5 (PDB ID: 6aei) is the most similar to that of TRPC1, and the similarity is 46.33%. Since reasonable conformations can be obtained with a model similarity above 30% (Bordoli et al. 2009), the modelling was performed with the short transient receptor potential channel 5 template to construct the TRPC1 protein 3D structure (Figure 1(A)). The Ramachandran plot was used to assess the quality of the model structure (Figure 1(B)). According to the Ramachandran plot, 91.44% of the TRPC1 amino acid residues are in the best region (green region). It is generally considered that a value larger than 90% indicates a reasonable protein model construction (Nagasundaram et al. 2016). Additionally, TRPC1 protein from homologous modelling has a certain influence on the accuracy of the model, and molecular dynamics simulation were performed using Gromacs 2020.1. As shown in Figure 1(C), the RMSD of the protein structure reached equilibrium after 80 ns during the simulation process, indicating that it was in a stable state at this time, and a stable conformation was randomly selected between 80 ns and 100 ns for subsequent docking experiments. The TRPC1 protein active pocket (Figure 2) was further predicted using POCASA to prepare for molecular docking.
Correlation between classical transient receptor potential channel 1 gene polymorphism and microalbuminuria in patients with primary hypertension
Published in Clinical and Experimental Hypertension, 2021
Yu Zhang, Bumairemu Maitikuerban, Yulan Chen, Yu Li, Yaping Cao, Xinjuan Xu
The contraction of renal microcirculation vascular smooth muscle cells and glomerular mesangial cells causes the interior of the glomerulus to stretch and bend, resulting in an increase in filtration pressure and a decrease in the surface area of capillaries; this contraction starts from the influx of Ca (2)+ (5,Presently, it has been confirmed that store-operated calcium channels (SOCC) are the main Ca2, influx channels on vascular smooth muscle cells and glomerular mesangial cells of renal microcirculation [6). Transient receptor potential channel 1 (TRPC1) is one of the common molecules involved in the formation of the SOCC complex (7). Interestingly, the TRPC1 channels are widely distributed in various vascular smooth muscle cells, and TRPC1 molecules have been detected in glomeruli and glomerular mesangial cells (8). It is well known that urinary microalbumin is a marker of endothelial dysfunction (9). The TRPC channels are critical Ca2+ channels in vascular endothelium. After activation of TRPC channels, intracellular calcium ions increase that induces actin polymerization and phosphorylation of myosin light chain through actin-myosin cross-bridge and actin polymerization to generate contractile force. The resulting contractile force contracts the cells and leads to the destruction of the endothelial cell barrier and increase the permeability (10). TRPC1 is mainly controlled by the gene, and hence, gene polymorphism may play a role in the production of microalbumin in patients with primary hypertension.
An overview of carbonic anhydrases and membrane channels of synoviocytes in inflamed joints
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
The TRPC1 and TRPC5 were expressed in secretory FLS76,77. The expression of oxidoreductase thioredoxin, a well-known oxidative stress marker, was increased in RA synovial fluids to counteract oxidative stress78–80. The thioredoxin was considered as a costimulatory component with cytokines in FLS81 and can be secreted82. Extracellular reduced form of thioredoxin enhanced the activities of TRPC1 and TRPC5 channels as new extracellular targets77. Inhibition of these channels by antibodies enhanced MMP secretion and suppressed the thioredoxin-mediated inhibitory effect on secretion77. More recently, the study of TRPC5 KO mice and inhibition of TRPC5 channels by antagonist addressed the enhanced inflamed joint and hyperalgesia76, suggesting that functional modulation of TRPC 1/5 could be considered as therapeutic targets for RA.