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J Biol Chem, Vol. 273, Issue 9, 5037-5046, February 27, 1998
From the Leicester University, Department of Cell Physiology and
Pharmacology, P. O. Box 138, Medical Sciences Building, University
Road, Leicester, LE1 9HN, United Kingdom
In this study we have quantitatively assessed the
basal turnover of phosphatidylinositol 4,5-bisphosphate
(PtdIns(4,5)P2) and M3-muscarinic
receptor-mediated changes in phosphoinositides in the human
neuroblastoma cell line, SH-SY5Y. We demonstrate that the
polyphosphoinositides represent a minor fraction of the total cellular
phosphoinositide pool and that in addition to rapid, sustained
increases in [3H]inositol phosphates dependent upon the
extent of receptor activation by carbachol, there are equally rapid and
sustained reductions in the levels of polyphosphoinositides. Compared
with phosphatidylinositol 4-phosphate (PtdIns(4)P),
PtdIns(4,5)P2 was reduced with less potency by carbachol
and recovered faster following agonist removal suggesting protection of
PtdIns(4,5)P2 at the expense of PtdIns(4)P and indicating
specific regulatory mechanism(s). This does not involve a pertussis
toxin-sensitive G-protein regulation of PtdIns(4)P 5-kinase. Using
wortmannin to inhibit PtdIns 4-kinase activity, we demonstrate that the
immediate consequence of blocking the supply of PtdIns(4)P (and
therefore PtdIns(4,5)P2) is a failure of agonist-mediated
phosphoinositide and Ca2+ signaling. The use of wortmannin
also indicated that PtdIns is not a substrate for receptor-activated
phospholipase C and that 15% of the basal level of
PtdIns(4,5)P2 is in an agonist-insensitive pool. We
estimate that the agonist-sensitive pool of PtdIns(4,5)P2 turns over every 5 s (0.23 fmol/cell/min) during sustained
receptor activation by a maximally effective concentration of
carbachol. Immediately following agonist addition,
PtdIns(4,5)P2 is consumed >3 times faster (0.76 fmol/cell/min) than during sustained receptor activation which
represents, therefore, utilization by a partially desensitized
receptor. These data indicate that resynthesis of PtdIns(4,5)P2 is required to allow full early and sustained
phases of receptor signaling. Despite the critical dependence of
phosphoinositide and Ca2+ signaling on
PtdIns(4,5)P2 resynthesis, we find no evidence that this
rate resynthesis is limiting for agonist-mediated responses.
Differential Regulation of Muscarinic Acetylcholine
Receptor-sensitive Polyphosphoinositide Pools and Consequences for
Signaling in Human Neuroblastoma Cells
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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