RT Journal Article
SR Electronic
T1 Identification of a Compound That Directly Stimulates Phospholipase C Activity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1043
OP 1050
DO 10.1124/mol.63.5.1043
VO 63
IS 5
A1 Yoe-Sik Bae
A1 Taehoon G. Lee
A1 Jun Chul Park
A1 Jung Ho Hur
A1 Youndong Kim
A1 Kyun Heo
A1 Jong-Young Kwak
A1 Pann-Ghill Suh
A1 Sung Ho Ryu
YR 2003
UL http://molpharm.aspetjournals.org/content/63/5/1043.abstract
AB 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 inm-3M3FBS–stimulated signaling by confirming the following: 1) pertussis toxin does not inhibitm-3M3FBS–induced [Ca2+]iincrease; 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 them-3M3FBS–induced [Ca2+]iincrease. We also observed that m-3M3FBS stimulated PLC activity in vitro. The purified isoforms of PLC that were tested (i.e., β2, β3, γ1, γ2, and δ1) were activated bym-3M3FBS and showed no isoform specificity. Taken together, these results demonstrate that m-3M3FBS modulates neutrophil functions by directly activating PLC. Becausem-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. The American Society for Pharmacology and Experimental Therapeutics