A Novel Receptor-mediated Regulation Mechanism of Type I Inositol Polyphosphate 5-Phosphatase by Calcium/Calmodulin-dependent Protein Kinase II Phosphorylation*

d-myo-inositol 1,4,5-trisphosphate (Ins(1,4,5)P3) andd-myo-inositol 1,3,4,5-tetrakisphosphate (Ins(1,3,4,5)P4) are both substrates of the 43-kDa type I inositol polyphosphate 5-phosphatase. Transient and okadaic acid-sensitive inhibition by 70–85% of Ins(1,4,5)P3 and Ins(1,3,4,5)P4 5-phosphatase activities was observed in homogenates from rat cortical astrocytes, human astrocytoma 1321N1 cells, and rat basophilic leukemia RBL-2H3 cells after incubation with carbachol. The effect was reproduced in response to UTP in rat astrocytic cells and Chinese hamster ovary cells overexpressing human type I 5-phosphatase. Immunodetection as well as mass spectrometric peptide mass fingerprinting and post-source decay (PSD) sequence data analysis after immunoprecipitation permitted unambiguous identification of the major native 5-phosphatase isoform hydrolyzing Ins(1,4,5)P3 and Ins(1,3,4,5)P4 as type I inositol polyphosphate 5-phosphatase. Inortho-32P-preincubated cells, the phosphorylated 43 kDa-enzyme could be identified after receptor activation by immunoprecipitation followed by electrophoretic separation. Phosphorylation of type I 5-phosphatase was blocked after cell preincubation in the presence of Ca2+/calmodulin kinase II inhibitors (i.e. KN-93 and KN-62). In vitro phosphorylation of recombinant type I enzyme by Ca2+/calmodulin kinase II resulted in an inhibition (i.e. 60–80%) of 5-phosphatase activity. In this study, we demonstrated for the first time a novel regulation mechanism of type I 5-phosphatase by phosphorylation in intact cells.

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