Regulation of intracellular Ca2+and gene expression by endothelin-1

Karin D. Rodland, Leslie Muldoon, Bruce E. Magun

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

In addition to its powerful vasoconstrictive activity, endothelin-1 (ET-1) is a potent agonist for stimulating a multitude of second messenger pathways. In the Rat-1 fibroblastic cell line, ET-1 induces a robust elevation of the intracellular levels of Ca2+, diacylglycerols (DGs), and inositol trisphosphate (IP3). Although low concentrations of ET-1 stimulate a significant increase in the rate of Ca2+influx, this Ca2+influx is not required for the observed increases in either IP3or DG levels following ET-1 treatment, as both of these effects are observed even in the absence of extracellular Ca2+. The ability of ET-1 to stimulate Ca2+influx shows a biphasic pattern, such that Ca2+influx is stimulated at low ET-1 concentrations and inhibited at high concentrations. Investigations of the molecular mechanisms underlying this biphasic response indicate that elevated intracellular Ca2+levels exert a negative feedback inhibition on Ca2+influx, which can be relieved by the chelation of intracellular Ca2+. The ability of ET-1 to activate a number of distinct signal transduction pathways appears to have direct functional significance in determining the targeting of ET-1 activation. Short-term effects of ET-1 stimulation such as the induction of gene expression appear to be independent of ET-1's ability to activate protein kinase C (PKC) by elevating DG levels, as depletion of PKC activity has little or no effect on gene expression. In contrast, the ability of ET-1 to induce the rapid expression of the VL30 gene is totally dependent upon the ability of ET-1 to elevate intracellular Ca2+levels above a specific threshold. Activation of PKC by ET-1. however, is essential for the long-term effects of ET-1 on cell proliferation and anchorage-independent growth, as the ability of ET-1 to promote DNA synthesis and to synergize with epidermal growth factor in augmenting anchorage-independent growth is significantly inhibited by prior PKC depletion. Thus, in fibroblasts, ET-1 appears to activate at least two bifurcating pathways: A Ca2+-sensitive pathway involved in the regulation of gene expression, and a PKC-dependent pathway required for the mitogenic effects of ET-1.

Original languageEnglish (US)
Pages (from-to)S89-S95
JournalJournal of Cardiovascular Pharmacology
Volume17
StatePublished - 1991

Fingerprint

Endothelin-1
Gene Expression
Protein Kinase C
Diglycerides
Gene Expression Regulation
Second Messenger Systems
Inositol
Growth
Epidermal Growth Factor

Keywords

  • Calcium
  • Endothelin-1
  • Gene expression

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Regulation of intracellular Ca2+and gene expression by endothelin-1. / Rodland, Karin D.; Muldoon, Leslie; Magun, Bruce E.

In: Journal of Cardiovascular Pharmacology, Vol. 17, 1991, p. S89-S95.

Research output: Contribution to journalArticle

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abstract = "In addition to its powerful vasoconstrictive activity, endothelin-1 (ET-1) is a potent agonist for stimulating a multitude of second messenger pathways. In the Rat-1 fibroblastic cell line, ET-1 induces a robust elevation of the intracellular levels of Ca2+, diacylglycerols (DGs), and inositol trisphosphate (IP3). Although low concentrations of ET-1 stimulate a significant increase in the rate of Ca2+influx, this Ca2+influx is not required for the observed increases in either IP3or DG levels following ET-1 treatment, as both of these effects are observed even in the absence of extracellular Ca2+. The ability of ET-1 to stimulate Ca2+influx shows a biphasic pattern, such that Ca2+influx is stimulated at low ET-1 concentrations and inhibited at high concentrations. Investigations of the molecular mechanisms underlying this biphasic response indicate that elevated intracellular Ca2+levels exert a negative feedback inhibition on Ca2+influx, which can be relieved by the chelation of intracellular Ca2+. The ability of ET-1 to activate a number of distinct signal transduction pathways appears to have direct functional significance in determining the targeting of ET-1 activation. Short-term effects of ET-1 stimulation such as the induction of gene expression appear to be independent of ET-1's ability to activate protein kinase C (PKC) by elevating DG levels, as depletion of PKC activity has little or no effect on gene expression. In contrast, the ability of ET-1 to induce the rapid expression of the VL30 gene is totally dependent upon the ability of ET-1 to elevate intracellular Ca2+levels above a specific threshold. Activation of PKC by ET-1. however, is essential for the long-term effects of ET-1 on cell proliferation and anchorage-independent growth, as the ability of ET-1 to promote DNA synthesis and to synergize with epidermal growth factor in augmenting anchorage-independent growth is significantly inhibited by prior PKC depletion. Thus, in fibroblasts, ET-1 appears to activate at least two bifurcating pathways: A Ca2+-sensitive pathway involved in the regulation of gene expression, and a PKC-dependent pathway required for the mitogenic effects of ET-1.",
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