Effects of phosphatidylinositol kinase inhibitors on the activation of the store-operated calcium current ICRAC in RBL-1 cells.
In electrically non-excitable cells, Ca2+ entry is mediated predominantly through the store-operated Ca2+ influx pathway, which is activated by emptying the intracellular Ca2+ stores following an increase in the levels of the second messenger inositol 1,4,5-trisphophate (InsP3). InsP3 is generated from the membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2). Recently, roles for other phosphoinositides (PIs) in store-operated Ca2+ influx have been suggested because inhibitors of PI kinases reduce Ca2+ influx when the latter is triggered independent of PIP2 hydrolysis. Using the whole-cell patch-clamp technique to record the store-operated Ca2+ current ICRAC in RBL-1 cells, we examined whether PIs are involved in linking store depletion to activation of CRAC channels. Of several structurally distinct PI kinase inhibitors, only one (LY294002) was able to reduce partially the extent of activation of ICRAC although this could not be reversed by exogenous phosphatidylinositol 3,4,5-trisphosphate (PIP3). Our findings suggest that, if a PI kinase is involved in activation of ICRAC in RBL-1 cells, it has a unique pharmacological profile. Alternative explanations for the results are discussed.
Straube
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Department of Physiology, University of Oxford, UK.
Parekh
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D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015471:Leukemia, Basophilic, Acute; D009025:Morpholines / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011794:Quercetin / Q000494:pharmacology; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D019870:1-Phosphatidylinositol 4-Kinase; D000730:Androstadienes; D002118:Calcium; D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011794:Quercetin; D019311:Staurosporine; D000077191:Wortmannin; C060974:phosphatidylinositol 3,4,5-triphosphate; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one