Conformational induction is the key process for activation of the AT1 receptor.
It is currently unclear whether activation of the AT1 receptor by agonists involves conformational selection or induction. We evaluated the pharmacological properties of wild type and N111G CAM human AT1 receptors stably expressed in HEK293 cells. Although [Sar1]-Ang II and Ang IV were full agonists at both receptors, the potency of Ang IV was 280-fold lower at the wild type receptor. [Sar1, Ile8]-Ang II was only a full agonist at the N111G CAM AT1 receptor. [Sar1]-Ang II and [Sar1, Ile8]-Ang II displayed similar high affinity binding to both receptors. In contrast, Ang IV displayed low affinity binding to the wild type and high affinity binding to the N111G CAM AT1 receptor. Based on these observations we provide strong evidence that conformational induction is the key process for activation of the AT1 receptor. Only by the creation of CAMs can conformational selection be envisaged to take place.
Ellis
James
J
Institute for Cardiovascular Research, University of Leeds, Leeds LS2 9JT, United Kingdom.
Warburton
Philip
P
Donnelly
Dan
D
Balmforth
Anthony J
AJ
D000804:Angiotensin II / Q000031:analogs & derivatives / Q000494:pharmacology; D001667:Binding, Competitive; D002460:Cell Line; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008954:Models, Biological; D011487:Protein Conformation; D044140:Receptor, Angiotensin, Type 1 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
D007295:Inositol Phosphates; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C012877:angiotensin II, des-Asp(1)-des-Arg(2)-Ile(5)-; C074793:angiotensin II, Sar(1)-