Summary
The oculocerebrorenal syndrome of Lowe (Lowe syndrome) is an X-linked disorder of phosphatidylinositol metabolism characterized by congenital cataracts, renal proximal tubulopathy and neurological deficits. The disorder is due to the deficiency of the phosphatidylinositol 4,5-bisphosphate (PIP2) 5-phosphatase, ocrl1. PIP2 is critical for numerous cellular processes, including cell signalling, actin reorganization and protein trafficking, and is chronically elevated in patients with Lowe syndrome. The elevation of PIP2 cells of patients with Lowe syndrome provides the unique opportunity to investigate the roles of this phospholipid in fundamental cellular processes. We previously demonstrated that ocrl1 deficiency causes alterations in the actin cytoskeleton. Since actin remodelling is strongly activated by [Ca+2], which increases in response to IP3 production, we hypothesized that altered calcium signalling might contribute to the observed abnormalities in actin organization. Here we report a specific increase in bradykinin-induced Ca+2 mobilization in Lowe fibroblasts. We show that the abnormal bradykinin signalling occurs in spite of normal total cellular receptor content. These data point to a novel role for ocrl1 in agonist-induced calcium release.
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Abbreviations
- 2-APB:
-
2-aminoethoxydiphenylborate
- EGF:
-
epidermal growth factor
- GPCR:
-
G-protein-coupled receptor
- PDGF:
-
platelet-derived growth factor
- PIP2 :
-
phosphatidylinositol 4,5-bisphosphate
- TGN:
-
trans-Golgi network
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Acknowledgements
This research was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health. The authors thank Dr James T. Russell NIH/National Institute of Child Health and Human Development, for his numerous helpful discussions, generously sharing advice throughout the course of this project, and for reviewing the manuscript. We thank Drs Paul Leo and Amalia Dutra for assistance with the confocal microscope and Julia Fekecs for graphics assistance. We also thank Dr. Christian Lavedan for thoughtful comments and critique of the manuscript.
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Communicating editor: Michael Gibson
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References to electronic databases: Oculocerebrorenal syndrome of Lowe: OMIM 309000. OCRL1: OMIM 300535. Phosphatidylinositol 4,5-bisphosphate 5-phosphatase: EC 3.1.3.36.
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Suchy, S.F., Cronin, J.C. & Nussbaum, R.L. Abnormal bradykinin signalling in fibroblasts deficient in the PIP2 5-phosphatase, ocrl1. J Inherit Metab Dis 32, 280–288 (2009). https://doi.org/10.1007/s10545-009-1058-3
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DOI: https://doi.org/10.1007/s10545-009-1058-3