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Research ArticleArticle

Gi- and Protein Kinase C-Mediated Heterologous Potentiation of Phospholipase C Signaling by G Protein-Coupled Receptors

Martina Schmidt, Barbara Lohmann, Kerstin Hammer, Stephan Haupenthal, Matthias Voß, Christoph Nehls and Karl H. Jakobs
Molecular Pharmacology June 1998, 53 (6) 1139-1148;
Martina Schmidt
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Barbara Lohmann
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Kerstin Hammer
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Stephan Haupenthal
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Matthias Voß
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Christoph Nehls
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Karl H. Jakobs
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Abstract

We recently reported that activation of the highly efficient phospholipase C (PLC) stimulatory m3 muscarinic acetylcholine receptor (mAChR) can induce a long-lasting Gi-mediated heterologous potentiation of PLC stimulation in human embryonic kidney (HEK) 293 cells, which was accompanied by an increased cellular level of the PLC substrate phosphatidylinositol-4,5-bisphosphate [PtdIns(4,5)P2]. Here, we examined whether such a potentiated PLC response is also induced by the rather poorly PLC stimulatory m2 mAChR and the endogenously expressed purinergic and lysophosphatidic acid receptors. Pretreatment of m2 mAChR-expressing HEK 293 cells for 2 min with carbachol, followed by agonist washout and measurement of PLC activity ≥40 min later, caused a long-lasting (up to ∼90 min) heterologous potentiation of receptor- and G protein-mediated PLC stimulation. A similar heterologous potentiation of receptor-mediated PLC stimulation was induced by short term activation of lysophosphatidic acid and purinergic receptors. Either of the three receptor agonists increased the cellular level of PtdIns(4,5)P2 by ∼50%. The mAChR-induced PLC potentiation was fully prevented by either pertussis toxin or the protein kinase C (PKC) inhibitors staurosporine and Gö 6976, which did not affect acute PLC stimulation. On the other hand, the rise in PtdIns(4,5)P2 was prevented only by combined treatment of HEK 293 cells with pertussis toxin and PKC inhibitors. In conclusion, we demonstrated that activation of poorly PLC stimulatory receptors can also induce a long-lasting Gi-mediated heterologous potentiation of PLC signaling in HEK 293 cells and that this novel PLC regulatory process is under the control of PKC.

Footnotes

  • Send reprint requests to: Dr. Martina Schmidt, Institut für Pharmakologie, Universitätsklinikum Essen, Hufelandstrasse 55, D-45122 Essen, Germany. E-mail:martina.schmidt{at}uni-essen.de

  • This work was supported by the Deutsche Forschungsgemeinschaft and the IFORES program of the Universitätsklinikum Essen.

  • Abbreviations:
    GTPγS
    guanosine-5′-O-(3-thio)triphosphate
    HBSS
    Hanks’ balanced salt solution
    HEPES
    4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
    Ins(1
    4,5)P3, inositol-1,4,5-trisphosphate
    LPA
    lysophosphatidic acid
    mAChR
    muscarinic acetylcholine receptor
    PKC
    protein kinase C
    PLC
    phospholipase C
    PMA
    phorbol-12-myristate-13-acetate
    PtdIns
    phosphatidylinositol
    PtdIns4P
    phosphatidylinositol-4-monophosphate
    PtdIns(4
    5)P2, phosphatidylinositol-4,5-bisphosphate
    PTX
    pertussis toxin
    HEK
    human embryonic kidney
    • Received September 16, 1997.
    • Accepted February 17, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (6)
Molecular Pharmacology
Vol. 53, Issue 6
1 Jun 1998
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Research ArticleArticle

Gi- and Protein Kinase C-Mediated Heterologous Potentiation of Phospholipase C Signaling by G Protein-Coupled Receptors

Martina Schmidt, Barbara Lohmann, Kerstin Hammer, Stephan Haupenthal, Matthias Voß, Christoph Nehls and Karl H. Jakobs
Molecular Pharmacology June 1, 1998, 53 (6) 1139-1148;

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Research ArticleArticle

Gi- and Protein Kinase C-Mediated Heterologous Potentiation of Phospholipase C Signaling by G Protein-Coupled Receptors

Martina Schmidt, Barbara Lohmann, Kerstin Hammer, Stephan Haupenthal, Matthias Voß, Christoph Nehls and Karl H. Jakobs
Molecular Pharmacology June 1, 1998, 53 (6) 1139-1148;
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