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Related Experiment Videos

The processing pathway of endothelin-1 production

T Kido1, T Sawamura, T Masaki

  • 1Department of Pharmacology, Faculty of Medicine, Kyoto University, Japan.

Journal of Cardiovascular Pharmacology
|May 22, 1998
PubMed
Summary
This summary is machine-generated.

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Furin-like convertase cleavage is essential for producing active endothelin-1 (ET-1). Mutations show cleavage at Arg92 is critical for endothelin-converting enzyme-1 (ECE-1) processing and ET-1 bioactivity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Endocrinology

Background:

  • Endothelin-1 (ET-1) production involves sequential proteolytic cleavages.
  • Key processing steps include signal peptidase, dibasic amino acid-specific convertases, and endothelin-converting enzyme (ECE).

Purpose of the Study:

  • To elucidate the relationship between pro-ET-1 processing by furin-like convertases and subsequent ECE-1 activity.
  • To determine the necessity of specific dibasic cleavage sites for ET-1 bioactivity.

Main Methods:

  • Site-directed mutagenesis of human preproET-1 cDNA to alter furin-like convertase recognition motifs (Arg49, Arg89).
  • Expression of mutant cDNAs in CHO-K1 cells.
  • Co-transfection with ECE-1 cDNA and assessment of ET-1 processing and receptor-mediated cellular responses.

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Main Results:

  • Mutations at Arg49 or Arg89 abolished processing at these sites, confirming furin-like convertase involvement.
  • Cleavage at Arg92 was essential for ECE-1 processing, while cleavage at Arg52 was not.
  • A large molecular weight form of ET-1 (Large ET-1), lacking Arg52 cleavage, did not induce a Ca2+ transient, indicating lack of bioactivity.

Conclusions:

  • Furin-like convertase-mediated cleavage is a prerequisite for generating biologically active endothelin-1.
  • Specific cleavage sites, particularly Arg92, are critical for proper ECE-1 processing and ET-1 function.