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The N‐terminal loop of endothelin: 2 sites to a story
Author(s) -
Compeer Matthijs G,
Suylen Dennis PL,
Hackeng Tilman M,
De Mey Jo GR
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.1115.19
Subject(s) - agonist , antagonist , chemistry , endothelin receptor , receptor , allosteric regulation , pharmacology , receptor antagonist , potency , endocrinology , medicine , biochemistry , in vitro
Endothelin‐1 (ET‐1) and (Trp 6 Leu 7 )Endothelin‐1 (ET‐2) are endogenous endothelin A (ET A )‐receptor agonists with comparable affinity and efficacy. However, the different amino acids on position 6 and 7 suggest differences in pharmacology. We used wire myography to investigate ET A ‐receptor mediated arterial contractions in a setting minimizing effects of the endothelium and of sensory‐motor nerves. Using ET‐1, ET‐2, the novel chimeras Trp 6 ET‐1 and Leu 7 ET‐1 and the selective ET A ‐receptor antagonist BQ123, we investigated the role of amino acids on position 6 and 7. We found that Leu 7 ET‐1 had a 30‐fold reduced contractile potency, compared to ET‐1. Trp 6 ET‐1 showed no apparent affinity at up to 256 nM. The antagonist affinity of BQ123 depended on the ET A ‐agonist used (pK B : Leu 7 ET‐1 > ET‐1 > ET‐2). The extent of antagonist‐induced relaxations of ET‐precontracted arteries also depended on the agonist used. Furthermore the preventive effects of the antagonist differed from its relaxing effects. Our results indicate roles of agonist N‐terminal loop amino acids in allosteric modulation of ET A ‐receptor function. When treating ET‐related diseases, taking into account which isoform is involved might improve treatment outcome. This study was performed within the framework of TI Pharma project T2‐301.