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Vol. 63, Issue 5, 1043-1050, May 2003
Medical Research Center for Cancer Molecular Therapy and Department
of Biochemistry, College of Medicine, Dong-A University, Busan, Korea
(Y.-S.B., J.-Y.K.); Sigmol Incorporation, Pohang, Korea (T.G.L.); and
Division of Molecular and Life Sciences, Pohang University of Science
and Technology, Pohang, Korea (J.C.P., J.H.H., Y.K., K.H., P.-G.S.,
S.H.R.)
Phosphoinositide-specific phospholipase C (PLC) plays a pivotal role in
the signal transduction of various cellular responses. However,
although it is undeniably important that modulators of PLC activity be
identified, no direct PLC activity modulator has been identified until
now. In this study, by screening more than 10,000 different compounds
in human neutrophils, we identified a compound that strongly enhances
superoxide-generating activity, which is well known to be
PLC-dependent. The active compound
2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide (m-3M3FBS) stimulated a transient intracellular calcium
concentration ([Ca2+]i) increase in
neutrophils. Moreover, m-3M3FBS stimulated the formation
of inositol phosphates in U937 cells, indicating that it stimulates PLC
activity. The compound showed no cell-type specificity in terms of
[Ca2+]i increase in the various cell lines
including leukocytes, fibroblasts, and neuronal cells. We also ruled
out the possible involvement of heterotrimeric G proteins in
m-3M3FBS-stimulated signaling by confirming the
following: 1) pertussis toxin does not inhibit m-3M3FBS-induced [Ca2+]i
increase; 2) m-3M3FBS does not stimulate cyclic AMP
generation; and 3) the inhibition of Gq by the regulator of
G protein-signaling 2 does not affect the
m-3M3FBS-induced [Ca2+]i
increase. We also observed that m-3M3FBS stimulated PLC
activity in vitro. The purified isoforms of PLC that were tested (i.e., 
2, 3, 
1, 2, and 
1) were activated by
m-3M3FBS and showed no isoform specificity. Taken
together, these results demonstrate that m-3M3FBS
modulates neutrophil functions by directly activating PLC. Because
m-3M3FBS is the first compound known to directly activate PLC, it should prove useful in the study of the basic molecular mechanisms of PLC activation and PLC-mediated cell signaling.
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