Functional significance of protein kinase A activation by endothelin-1 and ATP: Negative regulation of SRF-dependent gene expression by PKA

Amanda Davis, Kyle Hogarth, Darren Fernandes, Julian Solway, Jiaxin Niu, Vladimir Kolenko, Darren Browning, Joseph M. Miano, Sergei N. Orlov, Nickolai O. Dulin

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Endothelin-1 (ET1) and ATP stimulate contraction and hypertrophy of vascular smooth muscle cells (VSMC) by activating diverse signalling pathways. In this study, we show that in VSMC, ET1 and ATP stimulate transient and sustained activation of protein kinase A (PKA), respectively. Using a dominant negative PKA mutant (PKA-DN), we examined the functional significance of PKA activation in the signalling of ET1 and ATP. Overexpression of PKA-DN did not alter the ET1- or ATP-induced phosphorylation of the extracellular signal-regulated protein kinase, Erk2. ATP stimulated a profound, PKA-dependent activation of cAMP-response element (CRE), whereas the effect of ET1 was negligible. Both ET1 and ATP stimulated serum response factor (SRF)-dependent gene expression. Overexpression of PKA-DN potentiated the effects of ET1 and ATP on SRF activity, whereas stimulation of PKA by isoproterenol, forskolin or by overexpression of the PKA catalytic subunit decreased SRF activity. These data demonstrate that (i) PKA negatively regulates SRF activity and (ii) ET1 and ATP stimulate opposing pathways, whose balance determines the net activity of SRF.

Original languageEnglish (US)
Pages (from-to)597-604
Number of pages8
JournalCellular Signalling
Volume15
Issue number6
DOIs
StatePublished - Jun 1 2003

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Serum Response Factor
Endothelin-1
Cyclic AMP-Dependent Protein Kinases
Adenosine Triphosphate
Gene Expression
Proteins
Vascular Smooth Muscle
Smooth Muscle Myocytes
Extracellular Signal-Regulated MAP Kinases
Response Elements
Colforsin
Mutant Proteins
Isoproterenol
Protein Kinases
Hypertrophy
Catalytic Domain
Phosphorylation

Keywords

  • ATP
  • Endothelin
  • PKA
  • SRF
  • Vascular smooth muscle cells

ASJC Scopus subject areas

  • Cell Biology

Cite this

Functional significance of protein kinase A activation by endothelin-1 and ATP : Negative regulation of SRF-dependent gene expression by PKA. / Davis, Amanda; Hogarth, Kyle; Fernandes, Darren; Solway, Julian; Niu, Jiaxin; Kolenko, Vladimir; Browning, Darren; Miano, Joseph M.; Orlov, Sergei N.; Dulin, Nickolai O.

In: Cellular Signalling, Vol. 15, No. 6, 01.06.2003, p. 597-604.

Research output: Contribution to journalArticle

Davis, Amanda ; Hogarth, Kyle ; Fernandes, Darren ; Solway, Julian ; Niu, Jiaxin ; Kolenko, Vladimir ; Browning, Darren ; Miano, Joseph M. ; Orlov, Sergei N. ; Dulin, Nickolai O. / Functional significance of protein kinase A activation by endothelin-1 and ATP : Negative regulation of SRF-dependent gene expression by PKA. In: Cellular Signalling. 2003 ; Vol. 15, No. 6. pp. 597-604.
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