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12 Pharmacology of Human ETA and ETB Receptor Signalling VIA G-Protein and Beta-Arrestin Pathways
  1. JJ Maguire,
  2. RE Kuc,
  3. VR Pell ,
  4. AP Davenport
  1. Clinical Pharmacology Unit, University of Cambridge, Level 6 ACCI, Box 110 Addenbrooke’s Hospital, Cambridge CB2 0QQ UK

Abstract

The endothelin (ET) system is altered in cardiovascular diseases and ET receptor antagonists are licenced for treatment of pulmonary arterial hypertension (PAH). Endothelins act via two G-protein-coupled receptors (GPCRs), ETA and ETB. However, it is recognised that GPCRs may also activate signalling pathways in a G-protein-independent manner via beta-arrestin. Ligand-specific pathway modulation (biassed agonism/antagonism) may have therapeutic application and therefore we have investigated the potential for pathway bias of ET agonists and antagonists. Concentration-response curves were constructed to ET agonists using ETA and ETB beta-arrestin assays. ET receptor antagonists were tested for their ability to block ET-1 responses in each assay and agonist-dependence of the ETA selective antagonist BQ123 was investigated. These data were compared to results from binding experiments in human heart (that expresses both subtypes) and to ETA-mediated vasoconstrictor experiments in human saphenous vein. The relative potency of ET peptides in the ETA and ETB beta-arrestin assays was as expected. Interestingly, for ETA, compared to ET-1, all other agonists tested were partial agonists. Differences from the known pharmacology of antagonists were also revealed in the beta-arrestin assays. Specifically, BQ123 behaved as a negative allosteric modulator in the ETA assay, exhibiting agonist-dependent affinities. Bosentan was a potent ETA-selective antagonist in the beta-arrestin assay in contrast to its non-selective profile determined in human heart. The apparent ETA beta-arrestin bias of bosentan may contribute to its clinical effectiveness in PAH but further investigation of a role for functional selectivity and biassed signalling via the ET receptors in cardiovascular disease is required.

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