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Receptor externalization determines sustained contractile responses to endothelin-1 in the rat aorta
Ist Teil von
American Journal of Physiology: Cell Physiology, 1993-03, Vol.264 (3), p.C687-C693
Ort / Verlag
United States
Erscheinungsjahr
1993
Quelle
MEDLINE
Beschreibungen/Notizen
R. Marsault, E. Feolde and C. Frelin
Institut de Pharmacologie Moleculaire et Cellulaire, Universite de Nice-Sophia-Antipolis, Valbonne, France.
The role of receptor internalization and recycling in the vasoconstrictor
action of endothelin-1 (ET-1) is investigated using a combination of
biochemical and physiological experiments. The binding of 125I-ET-1 to
cultured aortic myocytes is first defined. Binding is rapidly followed by
an internalization of the peptide. Part of the receptor sites then slowly
reappears at the cell surface via a cycloheximide-insensitive mechanism.
Evidence that externalizing receptors are functional and can trigger
contractions is presented. Finally, the actions of
cyclo[D-Trp-D-Asp-Pro-D-Val-Leu] (BQ-123), an antagonist of ETA receptors,
are investigated. BQ-123 prevents 125I-ET-1 binding to aortic myocytes
(dissociation constant, 10 nM). It prevents the constricting action of ET-1
but not that of angiotensin II. BQ-123 also relaxes almost completely
aortic strips that have been precontracted by ET-1 irrespective of the time
of its addition. It is concluded that a recycling of internalized ET-1
receptors occurs in ET-1-treated aortic myocytes. This process amplifies
the action of the peptide and is probably responsible for the unique
contractile action of ET-1.