Control of PTH secretion by the TRPC1 ion channel

Familial Hypocalciuric Hypercalcemia (FHH) is a genetic condition associated with hypocalciuria, hypercalcemia and in some cases inappropriately high levels of circulating parathyroid hormone (PTH). FHH is associated with inactivating mutations in CaSR encoding the Ca2+ sensing receptor (CaSR), a G protein coupled receptor (GPCR) and GNA11 encoding G protein subunit alpha 11 (Gα11), implicating defective GPCR signaling as the root pathophysiology for FHH. However, the downstream mechanism by which CaSR activation inhibits PTH production/secretion is incompletely understood. Here, we show that mice lacking the transient receptor potential canonical channel 1 (TRPC1) develop chronic hypercalcemia, hypocalciuria, and elevated PTH levels mimicking human FHH. Ex vivo and in vitro studies reveal that TRPC1 serves a necessary and sufficient mediator to suppress PTH secretion from parathyroid glands (PTG) downstream of CaSR in response to high extracellular Ca2+ concentration. Gα11 physically interacts with both the N- and C-termini of TRPC1 and enhances CaSR-induced TRPC1 activity in transfected cells. These data identify TRPC1-mediated Ca2+ signaling as an essential component of the cellular apparatus controlling PTH secretion in the PTG downstream of CaSR

The sorting Nexin 3 retromer pathway regulates the cell surface localization and activity of a Wnt-activated polycystin channel complex

Autosomal dominant polycystic kidney disease (ADPKD) is caused by inactivating mutations in PKD1 (85%) or PKD2 (15%). The ADPKD proteins encoded by these genes, polycystin-1 (PC1) and polycystin-2 (PC2), form a plasma membrane receptor–ion channel complex. However, the mechanisms controlling the subcellular localization of PC1 and PC2 are poorly understood. Here, we investigated the involvement of the retromer complex, an ancient protein module initially discovered in yeast that regulates the retrieval, sorting, and retrograde transport of membrane receptors. Using yeast two-hybrid, biochemical, and cellular assays, we determined that PC2 binds two isoforms of the retromer-associated protein sorting nexin 3 (SNX3), including a novel isoform that binds PC2 in a direct manner. Knockdown of SNX3 or the core retromer protein VPS35 increased the surface expression of endogenous PC1 and PC2 in vitro and in vivo and increased Wnt-activated PC2-dependent whole-cell currents. These findings indicate that an SNX3-retromer complex regulates the surface expression and function of PC1 and PC2. Molecular targeting of proteins involved in the endosomal sorting of PC1 and PC2 could lead to new therapeutic approaches in ADPKD

Protective Effect of Increased Zinc Supply against Oxidative Damage of Sublingual Gland in Chronic Exposure to Cadmium: Experimental Study on Rats

Cadmium is one of the main chemical pollutants found in the daily environment of developed countries. Cigarettes are a significant source of that metal, which makes it important in terms of oral cavity health. The aim of this study was to determine if increased supply of zinc in chronic exposure to cadmium might protect the sublingual gland structure against oxidative damage. The experiment took 12 months and was conducted on 72 adult male rats. They were randomized into 9 groups. Eight groups received cadmium in drinking water (as CdCl2) at 5 or 50 mg Cd/dm3 and/or zinc (as ZnCl2) at 30 or 60 mg Zn/dm3. The control group received regular water. In the sublingual gland of all animal groups, levels of oxidative parameters were measured. The oxidative stress index was calculated as a TOS/TAS ratio. Cadmium exposure at 5 mg and 50 mg Cd/dm3 induced oxidative stress in the sublingual glands of the rats. Cadmium reduced the TAS and GSH levels and increased LPO, H2O2, TOS, and OSI. In cadmium exposure conditions, increasing the supply of zinc by 79% or 151%, as compared to the standard dietary intake of this microelement, completely prevented the reduction of TAS and GSH levels and accumulation of LPO, H2O2, and TOS in the examined gland at both exposure levels to that metal. The outcome data confirm the protective effect of increased zinc intake on the sublingual gland tissue in chronic cadmium exposure

Selected aspects of treatment of irreversible pulpitis

On the basis of the available literature on the subject, the causes and possible treatment options of irreversible pulpitis are discussed. The justifiability of the available treatment methods is also verified. The advantages and disadvantages of the available pulpitis treatment methods are discussed. The issue of toxicity of materials used in mortal endodontic treatment is highlighted. The causal relationship between endodontic treatment and focal diseases is explored

Selected aspects of treatment of irreversible pulpitis

On the basis of the available literature on the subject, the causes and possible treatment options of irreversible pulpitis are discussed. The justifiability of the available treatment methods is also verified. The advantages and disadvantages of the available pulpitis treatment methods are discussed. The issue of toxicity of materials used in mortal endodontic treatment is highlighted. The causal relationship between endodontic treatment and focal diseases is explored

Skeletal muscle response to endurance training in IL-6^{-/-} mice

We examined effects of moderate-intensity endurance training on muscle COX/CS activities and V’O2max in control WT and IL-6−/− mice. Animals were exercised for 10 weeks on treadmill for 1 h, 5 days a week at velocity of 6 m·min−1 which was increased by 0.5 m·min−1 every 2 weeks up to 8 m·min−1 . Training triggered an increase of enzyme activities in soleus muscle of WT mice (COX: 480.3±8.9 U·g−1 in sedentary group vs. 773.3±62.6 U·g−1 in trained group, P<0.05 and CS: 374.0±6.0 U·g−1 in sedentary group vs. 534.2±20.5 U·g−1 in trained group, P<0.01, respectively) whereas no changes were observed in soleus of IL6−/− mice. Moreover, in mixed gastrocnemius muscle of trained IL-6−/− mice enzyme activities tended to be lower (COX: 410.7±48.4 U·g−1 for sedentary vs. 277.0±36.5 U·g−1 for trained group and CS: 343.8±24.6 U·g−1 for sedentary vs. 251.7±27.1 U·g−1 for trained group). No changes in V’O2max were observed in WT and IL-6−/− mice after training. Concluding, moderate-velocity endurance training-induced increase in COX and CS activities in muscles of WT mice only which suggests that IL-6 regulates training-induced skeletal muscle responses to exercise. Copyright © 2015, Georg Thieme Verlag KG. All rights reserved

Control of PTH secretion by the TRPC1 ion channel

Familial Hypocalciuric Hypercalcemia (FHH) is a genetic condition associated with hypocalciuria, hypercalcemia and in some cases inappropriately high levels of circulating parathyroid hormone (PTH). FHH is associated with inactivating mutations in CaSR encoding the Ca2+ sensing receptor (CaSR), a G protein coupled receptor (GPCR) and GNA11 encoding G protein subunit alpha 11 (Gα11), implicating defective GPCR signaling as the root pathophysiology for FHH. However, the downstream mechanism by which CaSR activation inhibits PTH production/secretion is incompletely understood. Here, we show that mice lacking the transient receptor potential canonical channel 1 (TRPC1) develop chronic hypercalcemia, hypocalciuria, and elevated PTH levels mimicking human FHH. Ex vivo and in vitro studies reveal that TRPC1 serves a necessary and sufficient mediator to suppress PTH secretion from parathyroid glands (PTG) downstream of CaSR in response to high extracellular Ca2+ concentration. Gα11 physically interacts with both the N- and C-termini of TRPC1 and enhances CaSR-induced TRPC1 activity in transfected cells. These data identify TRPC1-mediated Ca2+ signaling as an essential component of the cellular apparatus controlling PTH secretion in the PTG downstream of CaSR