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lüll 80K-H as a new Ca2+ sensor regulating the activity of the epithelial Ca2+ channel transient receptor potential cation channel V5 (TRPV5) Gkika D; Mahieu F; Nilius B; Hoenderop JG; Bindels RJJ Biol Chem 2004[Jun]; 279 (25): 26351-7The epithelial Ca(2+) channel transient receptor potential cation channel V5 (TRPV5) constitutes the apical Ca(2+) entry pathway in the process of active Ca(2+) reabsorption. Ca(2+) influx through TRPV5 is tightly controlled by modulators of Ca(2+) homeostasis, including 1,25-dihydroxyvitamin D(3) and dietary Ca(2+). However, little is known about intracellular proteins that interact with TRPV5 and directly regulate the activation of this channel. By the use of cDNA microarrays, the present study identified 80K-H as the first protein involved in the Ca(2+)-dependent control of the epithelial Ca(2+) channel TRPV5. 80K-H was initially identified as a protein kinase C substrate, but its biological function remains to be established. We demonstrated a specific interaction between 80K-H and TRPV5, co-localization of both proteins in the kidney, and similar transcriptional regulation by 1,25-dihydroxyvitamin D(3) and dietary Ca(2+). Furthermore, 80K-H directly bound Ca(2+), and inactivation of its two EF-hand structures totally abolished Ca(2+) binding. Electrophysiological studies using 80K-H mutants showed that three domains of 80K-H (the two EF-hand structures, the highly acidic glutamic stretch, and the His-Asp-Glu-Leu sequence) are critical determinants for TRPV5 activity. Importantly, inactivation of the EF-hand pair reduced the TRPV5-mediated Ca(2+) current and increased the TRPV5 sensitivity to intracellular Ca(2+), accelerating the feedback inhibition of the channel. None of the 80K-H mutants altered the TRPV5 plasma membrane localization nor the association of 80K-H with TRPV5, suggesting that 80K-H has a direct effect on TRPV5 activity. In conclusion, we report a novel function for 80K-H as a Ca(2+) sensor controlling TRPV5 channel activity.|*Intracellular Signaling Peptides and Proteins[MESH]|*Membrane Proteins[MESH]|Absorption[MESH]|Animals[MESH]|Biotinylation[MESH]|Calcitriol/metabolism[MESH]|Calcium Channels/*metabolism[MESH]|Calcium/*metabolism[MESH]|Cell Membrane/metabolism[MESH]|DNA, Complementary/metabolism[MESH]|Electrophysiology[MESH]|Glucosidases[MESH]|Glutathione Transferase/metabolism[MESH]|Immunohistochemistry[MESH]|Kidney/metabolism[MESH]|Mice[MESH]|Mice, Inbred C57BL[MESH]|Models, Biological[MESH]|Mutation[MESH]|Myristoylated Alanine-Rich C Kinase Substrate[MESH]|Oligonucleotide Array Sequence Analysis[MESH]|Oocytes/metabolism[MESH]|Phosphoproteins/*physiology[MESH]|Precipitin Tests[MESH]|Protein Kinase C/metabolism[MESH]|Protein Structure, Tertiary[MESH]|RNA, Messenger/metabolism[MESH]|Reverse Transcriptase Polymerase Chain Reaction[MESH]|TRPV Cation Channels[MESH]|Tissue Distribution[MESH]|Xenopus[MESH] |