Abstract
The inositol (1,4,5) trisphosphate 3-kinases comprise a family of enzymes (A, B, and C) that phosphorylate the calcium mobilising molecule inositol (1,4,5) trisphosphate (IP3) to generate inositol (1,3,4,5) tetrakisphosphate. This molecule can function as a second messenger, but its roles are not completely understood. The A isoform of inositol (1,4,5) trisphosphate 3-kinase localises to filamentous actin within dendritic spines in the hippocampus and is implicated in the regulation of spine morphology and long term potentiation, however the mechanisms through which it signals in neuronal cells are not completely understood. We have used NGF driven neurite outgrowth from PC12 cells as a platform to examine the impact of signaling via inositol (1,4,5) trisphosphate 3-kinase activity in a neuronal cell. We have found that the catalytic activity of the enzyme opposes neurite outgrowth, whilst pharmacological inhibition of inositol (1,4,5) trisphosphate 3-kinase leads to a significant increase in neurite outgrowth, and we show that the reduction in neurite outgrowth in response to inositol (1,4,5) trisphosphate 3-kinase activity correlates with reduced ERK activity as determined by western blotting using phosphorylation-specific antibodies. Our findings suggest a novel neuronal signaling pathway linking metabolism of IP3 to signaling via ERK.
Highlights
Numerous ligand-operated signaling pathways involve the second-messenger inositol (1,4,5) trisphosphate (IP3), which is generated by the action of phospholipase C (PLC) on phopsphatidylinositol (4,5) bisphosphate (PIP2)
In order to investigate the effects of endogenous IP3 3-kinase activity in PC12 cells, we investigated the effects of a number of reported IP3 3-kinase inhibitors [24,27] on neurite outgrowth
We have demonstrated that elevated expression of IP3 3-KA dramatically inhibits NGF driven PC12 cell differentiation, and that this occurs principally as a result of the kinase activity of the enzyme
Summary
Numerous ligand-operated signaling pathways involve the second-messenger inositol (1,4,5) trisphosphate (IP3), which is generated by the action of phospholipase C (PLC) on phopsphatidylinositol (4,5) bisphosphate (PIP2). Three studies have implicated IP3 3-KB in the development of T-cells [9,10,11], and it has been implicated in B-cell development, selection and activation [12,13,14], as well as the regulation of myelopoesis and neutrophil signaling [15,16]. In B-cells, IP4 signals solely by inhibiting store operated calcium channels [13,14], whilst it is reported that IP4 negatively regulates PIP2 mediated activation of the GTPase activating protein Gap1IP4BP resulting in attenuated signaling via ERK [12].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
