The Active State of the AT₁ Angiotensin Receptor Is Generated by Angiotensin II Induction

Abstract

In the current model of receptor activation, the given hormone is not involved in the conversion of the inactive receptor (R) to the fully active state (R*). Rather, it preferentially selects the activated receptor conformation, thereby shifting the equilibrium toward R*. The hormone angiotensin II (Ang II) contains two residues, Tyr4 and Phe8, that are essential for agonism. We show that the conserved Asn111 in transmembrane helix III of the AT1 angiotensin receptor directly interacts with the Tyr4 side chain. A decrease in the size of the Asn111 side chain induces an intermediate activated receptor conformation (R'). The Ang II analogue [Sar1,Ile4,Ile8]Ang II fully activates the N111G mutant, indicating that either the transition from R' to R* or the stabilization of the R* state requires binding by Ang II but not its Tyr4 and Phe8 side chains. In contrast, [Sar1,Ile4,Ile8]Ang II binds to but does not activate the wild-type AT1 receptor (R), suggesting that in the wild-type receptor spontaneous occurrence of R' and R* states is rare. Thus, Ang II through interactions involving Tyr4 and Phe8 induces a transition from R to R' and through unspecified interactions induces transition from R' to R* states rather than stabilizing the spontaneously generated R* state by "conformational, selection".

Long Range Effect of Mutations on Specific Conformational Changes in the Extracellular Loop 2 of Angiotensin II Type 1 Receptor

“…1 is validated previously for compliance with experimentally determined interactions of AngII and losartan, as well as previous RCAM data (11,14). (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25). Functional interaction between receptor regions that are more than seven residues apart in the primary sequence and located at a distance greater than the hydrogen bonding distance (4 Å) in the tertiary structure is defined as long range interaction.…”

Gβγ-independent constitutive association of Gαswith SHP-1 and angiotensin II receptor AT2is essential in AT2-mediated ITIM-independent activation of SHP-1

“…First, in an AT 2 ͞AT 1 chimera receptor with the cytoloop 3 domain of AT 2 replaced by the corresponding region of AT 1 receptor, Ca 2ϩ movement was observed in the absence of Ang II stimulation (26). Second, Ang II binding profile has shown that in agreement with constitutively active AT 1 mutant N111G (27)(28)(29), AT 2 is insensitive to modifications of Ang II side chains at any position (22,30), suggesting that AT 2 receptor is already in a relaxed active state (R*). Third, Karnik's group has shown that AT 2 induces apoptosis in the absence of Ang II (25).…”

The angiotensin II type 1 receptor and receptor-associated proteins

“…B a s e d o n a n u m b e r o f pharmacological, mutagenesis and computer-oriented modeling studies [63][64][65][66][67][68][69][70][71][72][73][74][75][76], the general agreement is that a positively-charged residue of Lys199 on transmembrane domain (TM)-5 of the AT1 receptor interacts with the -carboxyl group of Phe8 in Ang II. This interaction is crucial for high affinity binding of Ang II to the receptor.…”