Resumen
The endothelin receptor A (ETA) and endothelin receptor B (ETB) are G protein-coupled receptors that are co-expressed in vascular smooth muscle cells. Endothelin-1 (ET-1) activates endothelin receptors to cause microvascular vasoconstriction. Previous studies have shown that heteromerization between ETA and ETB prolongs Ca2+ transients, leading to prolongation of Gαq-dependent signaling and sustained vasoconstriction. We hypothesized that these effects are in part mediated by the resistance of ETA/ETB heteromers to -arrestin recruitment and subsequent desensitization. Using bioluminescence resonance energy transfer 2 (BRET2), we found that ETB has a relatively equal affinity to form either homomers or heteromers with ETA when co-expressed in the human embryonic kidney 293 (HEK293) cells. When co-expressed, activation of ETA and ETB by ET-1 caused a heteromer-specific reduction and delay in β-arrestin-2 recruitment with a corresponding reduction and delay in ET-1-induced ETA/ETB co-internalization. Furthermore, the co-expression of ETA and ETB inhibited ET-1-induced β-arrestin-1-dependent extracellular signal-regulated kinase (ERK) phosphorylation while prolonging ET-1-induced Gαq-dependent ERK phosphorylation. ETA/ETB heteromerization mediates the long-lasting vasoconstrictor response to ET-1 by the prolongation of Gαq-dependent signaling and inhibition of β-arrestin function.
Idioma original | English |
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Páginas (desde-hasta) | 531-540 |
Número de páginas | 10 |
Publicación | Canadian Journal of Physiology and Pharmacology |
Volumen | 98 |
N.º | 8 |
DOI | |
Estado | Published - 2020 |
Nota bibliográfica
Funding Information:The authors acknowledge support from the Natural Sciences and Engineering Research Council of Canada (NSERC) to M.E.M.K. (grant No. 152148). A.M.B. is supported by a scholarship from King Abdulaziz University, Jeddah, Saudi Arabia.
Publisher Copyright:
© 2020, Canadian Science Publishing. All rights reserved.
ASJC Scopus Subject Areas
- Physiology
- Pharmacology
- Physiology (medical)