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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.
Oxidative stress impairs cGMP-dependent protein kinase activation and vasodilator-stimulated phosphoprotein serine-phosphorylation
Published in Clinical and Experimental Hypertension, 2019
Anees A. Banday, Mustafa F. Lokhandwala
Depletion of endoplasmic reticulum Ca2+ stores activates store-operated Ca2+ channels (SOC), a branch of TRPC. PKG stimulation regulates a variety of ion channels including Ca2+-activated K channels and TRPC (11,12,27). There are potential PKG sites on TRPC4, however, incubation of blood vessels with DETA NONOate did not phosphorylate TRPC4 or modulate its protein expression suggesting the involvement of an intermediate protein. There is evidence that phosphorylated VASP can interact with TRPC4 and modulate intracellular Ca2+. In the present study we also found that DETA NONOate increased the association of TRPC4 and phosphorylated VASP in vehicle-treated rats. However, DETA NONOate failed to cause VASP-239 phosphorylation or increase P-VASP-TRPC4 association in BSO-treated rats. This data shows that in normotensive animals NO-mediated PKG can regulate SOC via VASP-TRPC4 association. On the other, oxidative stress can reduce the NO-dependent PKG activation and abolish subsequent SOC regulation by blocking the P-VASP-TRPC4 association. An antioxidant can ameliorate the oxidative stress and restore SOC regulation via P-VASP-TRPC interaction.
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
Hypertension is the etiology and influencing factor of chronic kidney disease and the key to preventing cardiovascular disease (11). When the levels of urea and creatinine are increased, the glomerular filtration rate drops to 1/2-1/3rd of that of normal individuals. Concurrently, the kidney is severely damaged. Urinary microalbumin is negatively charged with a molecular weight of 6.9 kDa. Under normal circumstances, due to the negative charge of glomerular filtration membrane and basement membrane, and reabsorption of renal tubules, urinary albumin is rarely filtered. High intraglomerular transmembrane pressure and high filtration pressure in the early stage of primary hypertension destroy the glomerular filtration barrier and increase microalbuminuria. Therefore, the elevated level of microalbuminuria indicates early renal damage. In a large-scale population survey, Coresh et al. found that the incidence of microalbuminuria in patients with primary hypertension was 16% (12). The decline in albuminuria improves cardiovascular outcomes (13). Therefore, early diagnosis and treatment of microalbuminuria in patients with primary hypertension are crucial for improving the prognosis. Renal microcirculation vascular smooth muscle cells and glomerular mesangial cells regulate the glomerular filtration rate by changing the effective filtration area. SOCC is the main calcium channel on renal microcirculation vascular smooth muscle cells and glomerular mesangial cells. Previous studies have found that TRPC1 and TRPC4 are vital components of SOCC of human glomerular mesangial cells (14). In addition, in vitro experiments showed that TRPC1 is involved in regulating the contraction of glomerular mesangial cells (15) and therefore considered a novel target for the treatment of early renal damage in hypertension.