scholarly journals A polycystin-2 protein with modified channel properties leads to an increased diameter of renal tubules and to renal cysts

2021 ◽  
Author(s):  
Melanie Grosch ◽  
Katrin Brunner ◽  
Alexandr V. Ilyaskin ◽  
Michael Schober ◽  
Tobias Staudner ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Collecting Duct ◽  
Functional Characterization ◽  
Physiological Role ◽  
Renal Cysts ◽  
Receptor Potential ◽  
Xenopus Laevis Oocytes ◽  
Renal Tubules ◽  
Ion Translocation ◽  
Channel Properties

Mutations in the PKD2 gene cause autosomal-dominant polycystic kidney disease but the physiological role of polycystin-2, the protein product of PKD2, remains elusive. Polycystin-2 belongs to the transient receptor potential (TRP) family of non-selective cation channels. To test the hypothesis that altered ion channel properties of polycystin-2 compromise its putative role in a control circuit controlling lumen formation of renal tubular structures, we generated a mouse model in which we exchanged the pore loop of polycystin-2 with that of the closely related cation channel polycystin-2L1, thereby creating the protein polycystin-2poreL1. Functional characterization of this mutant channel in Xenopus laevis oocytes demonstrated that its electrophysiological properties differed from those of polycystin-2 but rather resembled the properties of polycystin-2L1, in particular regarding its permeability for Ca2+ ions. Homology modeling of the ion translocation pathway of polycystin-2poreL1 argues for a wider pore in polycystin-2poreL1 than in polycystin-2. In Pkd2poreL1 knock-in mice in which the endogenous polycystin-2 protein was replaced by polycystin-2poreL1 the diameter of collecting ducts was increased and collecting duct cysts developed in a strain-dependent fashion.

Nifedipine-activated Ca2+ permeability in newborn rat cortical collecting duct cells in primary culture

2001 ◽  
Vol 280 (5) ◽  
pp. C1193-C1203 ◽  
Author(s):  
Laura Valencia ◽  
Michel Bidet ◽  
Sonia Martial ◽  
Elsa Sanchez ◽  
Estela Melendez ◽  
...  
Keyword(s):  
Primary Culture ◽  
Transient Receptor Potential ◽  
Collecting Duct ◽  
Primary Cultures ◽  
Receptor Potential ◽  
Cortical Collecting Duct ◽  
Newborn Rat ◽  
Adult Rat ◽  
Intracellular Ca ◽  
Transient Receptor

To characterize Ca2+ transport in newborn rat cortical collecting duct (CCD) cells, we used nifedipine, which in adult rat distal tubules inhibits the intracellular Ca2+concentration ([Ca2+]i) increase in response to hormonal activation. We found that the dihydropyridine (DHP) nifedipine (20 μM) produced an increase in [Ca2+]i from 87.6 ± 3.3 nM to 389.9 ± 29.0 nM in 65% of the cells. Similar effects of other DHP (BAY K 8644, isradipine) were also observed. Conversely, DHPs did not induce any increase in [Ca2+]i in cells obtained from proximal convoluted tubule. In CCD cells, neither verapamil nor diltiazem induced any rise in [Ca2+]i. Experiments in the presence of EGTA showed that external Ca2+ was required for the nifedipine effect, while lanthanum (20 μM), gadolinium (100 μM), and diltiazem (20 μM) inhibited the effect. Experiments done in the presence of valinomycin resulted in the same nifedipine effect, showing that K+ channels were not involved in the nifedipine-induced [Ca2+]i rise. H2O2also triggered [Ca2+]i rise. However, nifedipine-induced [Ca2+]i increase was not affected by protamine. In conclusion, the present results indicate that 1) primary cultures of cells from terminal nephron of newborn rats are a useful tool for investigating Ca2+transport mechanisms during growth, and 2) newborn rat CCD cells in primary culture exhibit a new apical nifedipine-activated Ca2+ channel of capacitive type (either transient receptor potential or leak channel).

scholarly journals Regulation of calcium reabsorption along the rat nephron: a modeling study

2015 ◽  
Vol 308 (6) ◽  
pp. F553-F566 ◽  
Author(s):  
Aurélie Edwards
Keyword(s):  
Transient Receptor Potential ◽  
Stone Formation ◽  
Collecting Duct ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Transepithelial Transport ◽  
Thick Ascending Limb ◽  
Calcium Sensing ◽  
The Impact

We expanded a mathematical model of transepithelial transport along the rat nephron to include the transport of Ca2+ and probe the impact of calcium-sensing mechanisms on Ca2+ reabsorption. The model nephron extends from the medullary thick ascending limb (mTAL) to the inner medullary collecting duct (IMCD). Our model reproduces several experimental findings, such as measurements of luminal Ca2+ concentrations in cortical tubules, and the effects of furosemide or deletion of the transient receptor potential channel vanilloid subtype 5 (TRPV5) on urinary Ca2+ excretion. In vitro microperfusion of rat TAL has demonstrated that activation of the calcium-sensing receptor CaSR lowers the TAL permeability to Ca2+, PCaTAL (Loupy A, Ramakrishnan SK, Wootla B, Chambrey R, de la Faille R, Bourgeois S, Bruneval P, Mandet C, Christensen EI, Faure H, Cheval L, Laghmani K, Collet C, Eladari D, Dodd RH, Ruat M, Houillier P. J Clin Invest 122: 3355, 2012). Our results suggest that this regulatory mechanism significantly impacts renal Ca2+ handling: when plasma Ca2+ concentration ([Ca2+]) is raised by 10%, the CaSR-mediated reduction in PCaTAL per se is predicted to enhance urinary Ca2+ excretion by ∼30%. If high [Ca2+] also induces renal outer medullary potassium (ROMK) inhibition, urinary Ca2+ excretion is further raised. In vitro, increases in luminal [Ca2+] have been shown to activate H+-ATPase pumps in the outer medullary CD and to lower the water permeability of IMCD. Our model suggests that if these responses exhibit the sigmoidal dependence on luminal [Ca2+] that is characteristic of CaSR, then the impact of elevated Ca2+ levels in the CD on urinary volume and pH remains limited. Finally, our model suggests that CaSR inhibitors could significantly reduce urinary Ca2+ excretion in hypoparathyroidism, thereby reducing the risk of calcium stone formation.

Magnesium in Man: Implications for Health and Disease

2015 ◽  
Vol 95 (1) ◽  
pp. 1-46 ◽  
Author(s):  
Jeroen H. F. de Baaij ◽  
Joost G. J. Hoenderop ◽  
René J. M. Bindels
Keyword(s):  
Transient Receptor Potential ◽  
Growth Factor Receptor ◽  
Physiological Role ◽  
Calcineurin Inhibitors ◽  
Receptor Potential ◽  
Enzymatic Reactions ◽  
Comprehensive Overview ◽  
Transient Receptor Potential Melastatin ◽  
Health And Disease ◽  
Transient Receptor

Magnesium (Mg2+) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg2+availability has been proven to be disturbed during several clinical situations, serum Mg2+values are not generally determined in patients. This review aims to provide an overview of the function of Mg2+in human health and disease. In short, Mg2+plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg2+supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg2+transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg2+in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg2+research over the last few decades, focusing on the regulation of Mg2+homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.

scholarly journals Anatomical and functional characterization of a duodeno-pancreatic neural reflex that can induce acute pancreatitis

2013 ◽  
Vol 304 (5) ◽  
pp. G490-G500 ◽  
Author(s):  
Cuiping Li ◽  
Yaohui Zhu ◽  
Mohan Shenoy ◽  
Reetesh Pai ◽  
Liansheng Liu ◽  
...  
Keyword(s):  
Acute Pancreatitis ◽  
Cross Talk ◽  
Mechanical Stimulation ◽  
Transient Receptor Potential ◽  
Functional Characterization ◽  
Receptor Potential ◽  
Splanchnic Nerve ◽  
Mustard Oil ◽  
Myeloperoxidase Activity ◽  
Stimulation Of

Neural cross talk between visceral organs may play a role in mediating inflammation and pain remote from the site of the insult. We hypothesized such a cross talk exists between the duodenum and pancreas, and further it induces pancreatitis in response to intraduodenal toxins. A dichotomous spinal innervation serving both the duodenum and pancreas was examined, and splanchnic nerve responses to mechanical stimulation of these organs were detected. This pathway was then excited on the duodenal side by exposure to ethanol followed by luminal mustard oil to activate transient receptor potential subfamily A, member 1 (TRPA1). Ninety minutes later, pancreatic inflammation was examined. Ablation of duodenal afferents by resiniferatoxin (RTX) or blocking TRPA1 by Chembridge (CHEM)-5861528 was used to further investigate the duodeno-pancreatic neural reflex via TRPA1. ∼40% of dorsal root ganglia (DRG) from the spinal cord originated from both duodenum and pancreas via dichotomous peripheral branches; ∼50% splanchnic nerve single units responded to mechanical stimulation of both organs. Ethanol sensitized TRPA1 currents in cultured DRG neurons. Pancreatic edema and myeloperoxidase activity significantly increased after intraduodenal ethanol followed by mustard oil (but not capsaicin) but significantly decreased after ablation of duodenal afferents by using RTX or blocking TRPA1 by CHEM-5861528. We found the existence of a neural cross talk between the duodenum and pancreas that can promote acute pancreatitis in response to intraduodenal chemicals. It also proves a previously unexamined mechanism by which alcohol can induce pancreatitis, which is novel both in terms of the site (duodenum), process (neurogenic), and receptor (TRPA1).

scholarly journals The A563T variation of the renal epithelial calcium channel TRPV5 among African Americans enhances calcium influx

2009 ◽  
Vol 296 (5) ◽  
pp. F1042-F1051 ◽  
Author(s):  
Tao Na ◽  
Wei Zhang ◽  
Yi Jiang ◽  
Youyou Liang ◽  
He-Ping Ma ◽  
...  
Keyword(s):  
African Americans ◽  
High Frequency ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Hydroxyl Group ◽  
Xenopus Laevis Oocytes ◽  
Nucleotide Polymorphisms ◽  
Increased Sensitivity ◽  
Transient Receptor

The transient receptor potential cation channel, subfamily V, member 5 ( TRPV5) gene, which encodes the Ca2+ channel in the apical membrane of distal convoluted tubule and connecting tubule of the kidney, exhibits an unusually high frequency of nonsynonymous single nucleotide polymorphisms (SNPs) among African Americans. To assess the functional impacts of the nonsynonymous SNP variations in TRPV5, these variants were analyzed with radiotracer 45Ca2+ influx assay and the voltage-clamp technique using Xenopus laevis oocytes. Among the variations tested, including A8V, R154H, A563T, and L712F, the latter two significantly increased TRPV5-mediated Ca2+ influx. The A563T variant, which exists in African Americans with relative high frequency, exhibited increased Ca2+ influx at extracellular Ca2+ from 0.01 to 2 mM despite a lower expression level at the plasma membrane. This variant also exhibited a reduction in Na+ current as a result of increased sensitivity to extracellular Mg2+. By substituting threonine-563 (Thr563) with serine or valine residue, the bulky side chain of Thr563 was shown to facilitate Ca2+ transport, whereas the hydroxyl group of Thr563 is likely related to Mg2+ sensitivity. The A563T variant was capable of increasing TRPV5-mediated Ca2+ influx, even when it was expressed under conditions mimicking heterozygous or compound state with other variants. In conclusion, the A563T variant of TRPV5 significantly increased Ca2+ influx by affecting the Ca2+ permeation pathway. Thus the A563T variation in TRPV5 may contribute to the superior ability of renal Ca2+ conservation in African Americans.

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