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J. Biol. Chem., Vol. 276, Issue 18, 14814-14820, May 4, 2001
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From the Division of Pharmaceutical Sciences, College of Pharmacy,
University of Kentucky, Lexington, Kentucky 40536-0082
This study presents evidence that
phosphoinositide 3-kinase (PI3K) plays a concerted role with
phospholipase C
Phosphoinositide 3-Kinase Facilitates Antigen-stimulated
Ca2+ Influx in RBL-2H3 Mast Cells via a
Phosphatidylinositol 3,4,5-Trisphosphate-sensitive Ca2+
Entry Mechanism*
in initiating antigen-mediated
Ca2+ signaling in mast cells via a
phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3)-sensitive Ca2+ entry pathway.
Exogenous PI(3,4,5)P3 at concentrations close to its
physiological level induces instantaneous Ca2+ influx into
RBL-2H3 cells. This PI(3,4,5)P3-induced intracellular Ca2+ increase is independent of phospholipase C activity or
the depletion of internal stores. Moreover, inhibition of PI3K by
LY294002 or by overexpression of the dominant negative inhibitor 
p85
suppresses the Ca2+ response to the cross-linking of the
high affinity receptor for IgE (Fc
RI). Concomitant treatment of
RBL-2H3 cells with LY294002 or p85 and 2-aminoethyl diphenylborate,
a cell-permeant antagonist of D-myo-inositol
1,4,5-trisphosphate receptors, abrogates antigen-induced Ca2+ signals, whereas either treatment alone gives rise to
partial inhibition. Conceivably, PI(3,4,5)P3-sensitive
Ca2+ entry and capacitative Ca2+ entry
represent major Ca2+ influx pathways that sustain elevated
[Ca2+]i to achieve optimal physiological
responses. This study also refutes the second messenger role of
D-myo-inositol 1,3,4,5-tetrakisphosphate in
regulating FcRI-mediated Ca2+ response. Considering the
underlying mechanism, our data suggest that PI(3,4,5)P3
directly stimulates a Ca2+ transport system in plasma
membranes. Together, these data provide a molecular basis to account
for the role of PI3K in the regulation of FcRI-mediated
degranulation in mast cells.
*
This work was supported by National Institutes of Health
Grant GM53448.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: College of
Pharmacy, The Ohio State University, 500 West 12th Ave., Columbus, OH
43210-1291. Tel.: 614-688-4008; Fax: 614-688-8556; E-mail: chen@dendrite.pharmacy.ohio-state.edu.
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