Abnormal bradykinin signalling in fibroblasts deficient in the PIP(2) 5-phosphatase, ocrl1.
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 (PIP(2)) 5-phosphatase, ocrl1. PIP(2) 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 PIP(2) 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 IP(3) 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.
Suchy
S F
SF
Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, USA. sharon@genedx.com
Cronin
J C
JC
Nussbaum
R L
RL
D015153:Blotting, Western; D001920:Bradykinin / Q000494:pharmacology*; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics / Q000502:physiology*; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D006632:Histamine / Q000494:pharmacology; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000187:drug effects; D007476:Ionophores / Q000494:pharmacology; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D018002:Receptors, Bradykinin / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
D053496:Inositol 1,4,5-Trisphosphate Receptors; D007476:Ionophores; D010982:Platelet-Derived Growth Factor; D018002:Receptors, Bradykinin; D014404:Tubulin; D000001:Calcimycin; D006632:Histamine; D010744:Phosphoric Monoester Hydrolases; C075695:OCRL protein, human; D001920:Bradykinin; D002118:Calcium