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Functional Studies of PKD2 and PKD2L1 through Opening the Hydrophobic Activation Gate
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Wang Zheng, Lingyun Wang, Jingfeng Tang, Ji-Bin Peng, Xing-Zhen Chen
Although PKD2 and PKD2L1 have identical amino acid sequences in the cytoplasmic part of S6 in which gate residues are found, our data showed that PKD2L1 possesses a double-residue gate formed by L557/A558, while PKD2 has a single-residue (conventional) gate formed by L677 (corresponding to PKD2L1 L557). PKD2L1, but not PKD2, has detectable channel activity in the absence of an agonist,45,48 suggesting that PKD2L1 may have a larger pore than PKD2 in the resting state. Our structural data on PKD2-activated mutant F604P showed a larger pore size than the WT channel and the presence of π- to α-helical transition in the S6 helix from WT PKD2 to mutant F604P, which accompanies S6 twisting. We wondered whether this S6 twisting is sufficiently significant so that mutant F604P would possess a double-residue gate. Indeed, our functional study showed that in PKD2 mutant F604P, both F676 and A677 exhibit characteristics of being gate residues (Figure 5.8). Thus, compared with WT PKD2, mutant F604P is more similar to PKD2L1 in terms of the pore size and possession of a double-residue gate. Of note, based on similar approaches, we also found single-residue gates in TRPV4, -M8, and -C4 and double-residue gate in TRPV5 and -V6.46
Ion Channels of Reward Pathway in Drug Abuse
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Transient receptor potential (TRP) channels are a large family of non-selective cation channels. Besides traditional ligand-gated opening, mechanical force, chemical stress, and temperature also can lead to channel opening. Most TRP channels are permeable to Ca2+ with the exceptions of TRPM4 and TRPM5, which are only permeable to monovalent cations. The TRP superfamily contains six groups: TRPA (ankyrin), TRPC (canonical), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPV (vanilloid). TRP channels were first identified in Drosophila melanogaster, and studies have found around 30 channels in mammals belonging to this superfamily. The diverse activation mechanisms and expression of these channels make them involved in a wide range of activities of the central and peripheral nervous systems. However, the roles of these channels in drug abuse have only recently begun to be explored, with one of the most thoroughly studied families of TRP channels in drug abuse being the TRPV family. The TRPV family contains six mammalian members: TRPV1-6. TRPV1-4 are all heat-activated channels, which exhibit cation non-selectivity and modest Ca2+ permeability. TRPV5 and TRPV6 are the only highly Ca2+-selective channels in the TRP family, and both are regulated by [Ca2+]i. In contrast with other TRPVs, the temperature sensitivity of TRPV5 and TRPV6 is relatively low. TRPV1-4 are also sensitive to a broad array of endogenous and synthetic ligands. For example, TRPV1 is activated by capsaicin, heat (≥43°C), and many other chemicals, including an endocannabinoid, anandamide; the topical analgesic, camphor; piperine in black pepper; and allicin in garlic (Caterina et al. 1997; Zygmunt et al. 1999; Xu, Blair, and Clapham 2005; McNamara, Randall, and Gunthorpe 2005; Macpherson et al. 2005). Activation of TRPV1 leads to membrane depolarization, and TRPV1-mediated current can be facilitated by extracellular acidification (Xu, Blair, and Clapham 2005). A pH change to <6, ethanol, and nicotine also have similar effects on TRPV1 activity (Trevisani et al. 2002; Liu et al. 2004).
Protective Effect of Calcitriol on Organ Damage Induced by 5-Fluorouracil Treatment
Published in Nutrition and Cancer, 2021
Szu-Chi Chen, Chun-Yen Ke, Yi-Maun Subeq, Wan-Ting Yang, Shyh-Geng Huang, An-Suey Shiao, Ru-Ping Lee
The overexpression of specific calcium channels in some cancer types has been discussed in previous studies. Calcium metabolism in a cancer state is a product of the tumor microenvironment and it directly affects processes in tumor proliferation and invasiveness (40). The inhibition of tumor calcium channels has been used to decrease tumor calcium intake as a cancer therapy strategy, for instance, to inhibit the transmembrane protein TRPV (transient receptor potential vanilloid) channel (40). TRPV overexpression has been reported in the proliferation of some malignant cancers. For example, the effects of TRPV6 inhibitor on cytosolic calcium signaling can contribute to preventing the proliferation of cancer cells (40). In addition, vitamin D has been found to decrease TRPV6 expression in human renal cell carcinoma (RCC) (41), and vitamin D receptor (VDR) functions as a tumor suppressor in RCC cells. Indeed, the overexpression of VDR significantly inhibits RCC cell proliferation, migration, and invasion by regulating the expression of TRPV5 (42). Taken together, these findings suggest that the administration of vitamin D3 could potentially show even better functionality in a cancer condition than in the normal rat physiology described in this study.
The use of LP533401 as a therapeutic option for renal osteodystrophy affects, renal calcium handling, vitamin D metabolism, and bone health in uremic rats
Published in Expert Opinion on Therapeutic Targets, 2019
Dariusz Pawlak, Tomasz Domaniewski, Beata Znorko, Krystyna Pawlak
Regulation of calcium reabsorption in the kidney is essential for the maintenance of physiological serum calcium concentrations and occurs via para- and transcellular ways. Transcellular (active) calcium reabsorption process takes place in the distal convoluted tubule and connecting tubule of the kidney. Luminal calcium (Ca2+) enters these tubular cells via the epithelial Ca2+ channels: transient receptor potential vanilloid receptor subtypes 5 and 6 (TRPV5 and TRPV6). Next, Ca2+ is transported from the apical to the basolateral side of the cell in association with Ca2+-carrier proteins: calbindin-D28k (CaBP-28K) and calbindin-D9k (CaBP-9k). Finally, Ca2+ is extruded into the blood compartment via the Na+/Ca2+-exchanger (NCX1) and the plasma membrane Ca2+-ATPase (PMCA1b) [7–11].
The impact of shrunken pore syndrome in patient with rheumatic diseases on bone mineral metabolism
Published in Scandinavian Journal of Clinical and Laboratory Investigation, 2021
Ichiro Yoshii, Susumu Nishiyama
PTH promotes binding to the PTH receptor on the osteoblast membrane. The induced RANKL binds to the RANKL receptor RANK on the osteoclast precursor membrane and stimulates calcium mobilization from the bone into the blood [28]. At the same time, the activated transient receptor potential cation channel subfamily V member 5 (TRPV5) stimulates calcium reabsorption of the allantoic membrane calcium channels in the distal renal tubule [29]. On the other hand, PTH suppresses the action of the Na-Pi co-transporter in the proximal tubule to reduce phosphorus reabsorption [30].