title: Manifold active-state conformations in GPCRs: agonist-activated constitutively active mutant AT1 receptor preferentially couples to Gq compared to the wild-type AT1 receptor.
abstract: The angiotensin II type I (AT(1)) receptor mediates regulation of blood pressure and water-electrolyte balance by Ang II. Substitution of Gly for Asn(111) of the AT(1) receptor constitutively activates the receptor leading to Gq-coupled IP(3) production independent of Ang II binding. The Ang II-activated conformation of the AT1(N111G) receptor was proposed to be similar to that of the wild-type AT(1) receptor, although, various aspects of the Ang II-induced conformation of this constitutively active mutant receptor have not been systematically studied. Here, we provide evidence that the conformation of the active state of the wild-type and the constitutively active AT(1) receptors are different. Upon Ang II binding an activated conformation of the wild-type AT(1) receptor activates G protein and recruits beta-arrestin. In contrast, the agonist-bound AT1(N111G) mutant receptor preferentially couples to Gq and is inadequate in beta-arrestin recruitment.
authors.affiliation: Department of Molecular Cardiology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. leec@daegu.ac.kr
authors.forename: ChangWoo
authors.initials: C
authors.lastname: Lee
authors.forename: Si Ae
authors.initials: SA
authors.lastname: Hwang
authors.forename: Sei-Heon
authors.initials: SH
authors.lastname: Jang
authors.forename: Hye-Shin
authors.initials: HS
authors.lastname: Chung
authors.forename: Manjunatha B
authors.initials: MB
authors.lastname: Bhat
authors.forename: Sadashiva S
authors.initials: SS
authors.lastname: Karnik
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019390:Arrestins / Q000378:metabolism; D001216:Asparagine; D001665:Binding Sites; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling; D003001:Cloning, Molecular; D005998:Glycine; D007700:Kinetics; D016297:Mutagenesis, Site-Directed; D011487:Protein Conformation; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D000071557:beta-Arrestins
chemical_list: D019390:Arrestins; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D011994:Recombinant Proteins; D000071557:beta-Arrestins; D001216:Asparagine; D002118:Calcium; D005998:Glycine