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Tissue kallikrein stimulates Ca(2+) reabsorption via PKC-dependent plasma membrane accumulation of TRPV5 Gkika D; Topala CN; Chang Q; Picard N; Thebault S; Houillier P; Hoenderop JG; Bindels RJEMBO J 2006[Oct]; 25 (20): 4707-16The transient receptor potential vanilloid 5 (TRPV5) channel determines urinary Ca(2+) excretion, and is therefore critical for Ca(2+) homeostasis. Interestingly, mice lacking the serine protease tissue kallikrein (TK) exhibit robust hypercalciuria comparable to the Ca(2+) leak in TRPV5 knockout mice. Here, we delineated the molecular mechanism through which TK stimulates Ca(2+) reabsorption. Using TRPV5-expressing primary cultures of renal Ca(2+)-transporting epithelial cells, we showed that TK activates Ca(2+) reabsorption. The stimulatory effect of TK was mimicked by bradykinin (BK) and could be reversed by application of JE049, a BK receptor type 2 antagonist. A cell permeable analog of DAG increased TRPV5 activity within 30 min via protein kinase C activation of the channel since mutation of TRPV5 at the putative PKC phosphorylation sites S299 and S654 prevented the stimulatory effect of TK. Cell surface labeling revealed that TK enhances the amount of wild-type TRPV5 channels, but not of the TRPV5 S299A and S654A mutants, at the plasma membrane by delaying its retrieval. In conclusion, TK stimulates Ca(2+) reabsorption via the BK-activated PLC/DAG/PKC pathway and the subsequent stabilization of the TRPV5 channel at the plasma membrane.|*Signal Transduction/drug effects/genetics[MESH]|Amino Acid Substitution[MESH]|Animals[MESH]|Anti-Inflammatory Agents, Non-Steroidal/pharmacology[MESH]|Bradykinin B2 Receptor Antagonists[MESH]|Bradykinin/analogs & derivatives/metabolism/pharmacology[MESH]|Calcium Channels/deficiency/genetics/*metabolism[MESH]|Calcium/*metabolism[MESH]|Cell Line[MESH]|Cell Membrane/genetics/metabolism[MESH]|Enzyme Activation/drug effects/genetics[MESH]|Humans[MESH]|Kallikreins/*metabolism[MESH]|Kidney Tubules/cytology/*metabolism[MESH]|Mice[MESH]|Mice, Knockout[MESH]|Mutation, Missense[MESH]|Oximes/pharmacology[MESH]|Protein Kinase C/antagonists & inhibitors/*metabolism[MESH]|Rabbits[MESH]|Receptor, Bradykinin B2/agonists/metabolism[MESH]|TRPV Cation Channels/deficiency/genetics/*metabolism[MESH]|Vasodilator Agents/pharmacology[MESH] |
