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Molecular Pharmacology

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Research ArticleArticle

Identification of a Compound That Directly Stimulates Phospholipase C Activity

Yoe-Sik Bae, Taehoon G. Lee, Jun Chul Park, Jung Ho Hur, Youndong Kim, Kyun Heo, Jong-Young Kwak, Pann-Ghill Suh and Sung Ho Ryu
Molecular Pharmacology May 2003, 63 (5) 1043-1050; DOI: https://doi.org/10.1124/mol.63.5.1043
Yoe-Sik Bae
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Taehoon G. Lee
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Jun Chul Park
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Jung Ho Hur
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Youndong Kim
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Kyun Heo
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Jong-Young Kwak
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Pann-Ghill Suh
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Sung Ho Ryu
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Abstract

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.

Footnotes

  • This work was supported by grant 01-PJ4-PG4-01VN01-0319 from the Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea.

  • Abbreviations:
    PI
    phosphoinositide
    PLC
    phospholipase C
    PIP2
    phosphatidylinositol bisphosphate
    [Ca2+]i
    intracellular calcium concentration
    m-3M3FBS
    2,4,6-trimethyl-N-(meta-3-trifluoromethyl-phenyl)-benzenesulfonamide
    PTX
    pertussis toxin
    o-3M3FBS
    2,4,6-trimethyl-N-(ortho-3-trifluoromethyl-phenyl)-benzenesulfonamide
    RGS
    regulators of G protein signaling
    WKYMVm
    Trp-Lys-Tyr-Met-Val-d-Met-CONH2
    PI3-kinase
    phosphoinositide 3-kinase
    GFP
    green fluorescent protein
    • Received September 13, 2002.
    • Accepted January 22, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (5)
Molecular Pharmacology
Vol. 63, Issue 5
1 May 2003
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Research ArticleArticle

Identification of a Compound That Directly Stimulates Phospholipase C Activity

Yoe-Sik Bae, Taehoon G. Lee, Jun Chul Park, Jung Ho Hur, Youndong Kim, Kyun Heo, Jong-Young Kwak, Pann-Ghill Suh and Sung Ho Ryu
Molecular Pharmacology May 1, 2003, 63 (5) 1043-1050; DOI: https://doi.org/10.1124/mol.63.5.1043

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Research ArticleArticle

Identification of a Compound That Directly Stimulates Phospholipase C Activity

Yoe-Sik Bae, Taehoon G. Lee, Jun Chul Park, Jung Ho Hur, Youndong Kim, Kyun Heo, Jong-Young Kwak, Pann-Ghill Suh and Sung Ho Ryu
Molecular Pharmacology May 1, 2003, 63 (5) 1043-1050; DOI: https://doi.org/10.1124/mol.63.5.1043
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