Identification of the receptor subtype responsible for endothelin-mediated protein kinase C activation and atrial natriuretic factor secretion from atrial myocytes

C. E. Irons, S. F. Murray, C. C. Glembotski

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Endothelin-1 (ET-1) is a potent stimulator of atrial natriuretic factor (ANF) secretion from myocardial cells. In heart tissue there are two ET receptor subtypes (ET(A)-R and ET(B)-R), which can be pharmacologically distinguished by the ET isopeptides ET-1 and ET-3. However, the identification of the ET-R subtype responsible for the rapid enhancement of ANF release, which occurs within minutes of exposing cardiac myocytes to ET, has not been investigated. In the present study ET-1 was about 100-fold more potent than ET-3 at stimulating membrane phosphoinositide hydrolysis, protein kinase C activation, and ANF release from purified primary atrial myocytes. These responses were completely abolished by BQ123, an ET(A)-R antagonist. Radioligand binding analyses showed that competitor peptides displaced 125I-ET-1 binding to atrial myocyte ET-Rs with a rank order of potency of ET-1 >> BQ123 > ET-3, a characteristic ET(A)-R pharmacological profile. While neither ET-1 or ET-3 altered forskolin-stimulated cAMP levels, suggesting the absence of the ET(B)-R, basal cAMP levels were also unaffected by the ETs. Northern analysis using ET-R subtype-specific probes demonstrated that the ET(A)-R transcript was present in the cultures at levels at least 50-fold greater than the ET(B)-R transcript. These findings demonstrate that the stimulation of the phosphatidylinositol/protein kinase C pathway, which is required for maximal ET-stimulated ANF release from primary atrial myocytes, is associated with the activation of only the ET(A)-R, thus defining a specific function for an endogenous ET-R in myocardial cells.

Original languageEnglish (US)
Pages (from-to)23417-23421
Number of pages5
JournalJournal of Biological Chemistry
Volume268
Issue number31
StatePublished - 1993
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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