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lüll ATP modulates Ca2+ uptake by TRPV6 and is counteracted by isoform-specific phosphorylation Al-Ansary D; Bogeski I; Disteldorf BM; Becherer U; Niemeyer BAFASEB J 2010[Feb]; 24 (2): 425-35Ca(2+) homeostasis requires balanced uptake and extrusion, and dysregulation leads to disease. TRPV6 channels are homeostasis regulators, are upregulated in certain cancers, and show an unusual allele-specific evolution in humans. To understand how Ca(2+) uptake can be adapted to changes in metabolic status, we investigate regulation of Ca(2+)-influx by ATP and phosphorylation. We show that ATP binds to TRPV6, reduces whole-cell current increments, and prevents channel rundown with an EC(50) of 380 microM. By using both biochemical binding studies and patch-clamp analyses of wild-type and mutant channels, we have mapped one relevant site for regulation by ATP to residues within the ankyrin repeat domain (ARD) and identify an additional C-terminal binding region. Stimulation of PKC largely prevented the effects of ATP. This regulation requires PKC(betaII) and defined phosphorylation sites within the ARD and the C-terminus. Both regulatory sites act synergistically to constitute a novel mechanism by which ATP stabilizes channel activity and acts as a metabolic switch for Ca(2+) influx. Decreases in ATP concentration or activation of PKC(betaII) disable regulation of the channels by ATP, rendering them more susceptible to inactivation and rundown and preventing Ca(2+) overload.|Adenosine Triphosphate/*metabolism[MESH]|Calcium Channels/*metabolism[MESH]|Calcium/*metabolism[MESH]|Cell Line[MESH]|Humans[MESH]|Isoenzymes/metabolism[MESH]|Patch-Clamp Techniques[MESH]|Phosphorylation[MESH]|Protein Kinase C beta[MESH]|Protein Kinase C/metabolism[MESH]|TRPV Cation Channels/*metabolism[MESH] |