期刊
CELL CALCIUM
卷 45, 期 4, 页码 331-339出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ceca.2008.12.003
关键词
CaR; TRPV5; Distal convoluted tubule; Neomycin; Electrophysiology
类别
资金
- Netherlands Organization for Scientific Research [NWO-ALW 814.02.001]
- Dutch Kidney Foundation [C03.6017]
- United Kingdom Department of Trade and Industry [K0508]
- European Science Foundation
The extracellular Ca2+-sensing receptor (CaR) is a key-player in plasma Ca2+ 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 Ca2+ reabsorption, but the function of the CaR has remained unclear in these segments. Here, the Ca2+-selective Transient Receptor Potential Vanilloid-subtype 5 channel (TRPV5) determines active Ca2+ 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-ratio metric measurements we demonstrate that activation of the CaR leads to elevated TRPV5-mediated currents and increases intracellular Ca2+ 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, CaRR185Q. 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 Ca2+ influx via a PMA-insensitive PKC isoform pathway. (C) 2008 Elsevier Ltd. All rights reserved.
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