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Activation of the Ca2+-sensing receptor stimulates the activity of the epithelial Ca2+ channel TRPV5 Topala CN; Schoeber JP; Searchfield LE; Riccardi D; Hoenderop JG; Bindels RJCell Calcium 2009[Apr]; 45 (4): 331-9The extracellular Ca(2+)-sensing receptor (CaR) is a key-player in plasma Ca(2+) homeostasis. It is essentially expressed in the parathyroid glands and along the kidney nephron. The distal convoluted tubules (DCT) and connecting tubules (CNT) in the kidney are involved in active Ca(2+) reabsorption, but the function of the CaR has remained unclear in these segments. Here, the Ca(2+)-selective Transient Receptor Potential Vanilloid-subtype 5 channel (TRPV5) determines active Ca(2+) reabsorption by forming the apical entry gate. In this study we show that the CaR and TRPV5 co-localize at the luminal membrane of DCT/CNT. Furthermore, by patch-clamp and Fura-2-ratiometric measurements we demonstrate that activation of the CaR leads to elevated TRPV5-mediated currents and increases intracellular Ca(2+) concentrations in cells co-expressing TRPV5 and CaR. Activation of CaR initiated a signaling cascade that activated phorbol-12-myristate-13-acetate (PMA)-insensitive protein kinase C (PKC) isoforms. Importantly, mutation of two putative PKC phosphorylation sites, S299 and S654, in TRPV5 prevented the stimulatory effect of CaR activation on channel activity, as did a dominant negative CaR construct, CaR(R185Q). Interestingly, the activity of TRPV6, TRPV5' closest homologue, was not affected by the activated CaR. We conclude that activation of the CaR stimulates TRPV5-mediated Ca(2+) influx via a PMA-insensitive PKC isoform pathway.|*Ion Channel Gating[MESH]|Animals[MESH]|Cell Membrane/drug effects/metabolism[MESH]|Cell Polarity/drug effects[MESH]|Epithelial Cells/cytology/drug effects/enzymology/*metabolism[MESH]|Humans[MESH]|Isoenzymes/metabolism[MESH]|Kidney Tubules, Distal/cytology/drug effects/metabolism[MESH]|Mice[MESH]|Mutant Proteins/metabolism[MESH]|Phosphorylation/drug effects[MESH]|Protein Kinase C/metabolism[MESH]|Protein Transport/drug effects[MESH]|Rabbits[MESH]|Receptors, Calcium-Sensing/*metabolism[MESH]|Signal Transduction/drug effects[MESH]|TRPV Cation Channels/*metabolism[MESH]|Tetradecanoylphorbol Acetate/pharmacology[MESH] |
