Assessment of inverse agonism for the angiotensin II type 1 receptor.
The angiotensin II (AngII) type 1 (AT₁) receptor is a seven-transmembrane G-protein-coupled receptor that plays a regulatory role in the physiological and pathological processes of the cardiovascular system. AT₁ receptor inherently shows constitutive activity even in the absence of AngII, and it is activated not only by AngII but also by AngII-independent mechanisms. Especially, mechanical stress induces cardiac hypertrophy through activation of AT₁ receptor without the involvement of AngII. These AngII-independent activities of AT₁ receptor can be inhibited by inverse agonists, but not by neutral antagonists. In this chapter, we describe the methods used for biochemical assessment of inverse agonism of a ligand for AT₁ receptor. Their applications will improve our understanding of receptor activation and inactivation at a molecular level, and contribute to the development of AT₁ receptor blockers possessing superior therapeutic efficacy in cardiovascular diseases.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Yamadaoka, Suita, Osaka, Japan.
Hiroshi
H
Akazawa
Noritaka
N
Yasuda
Shin-ichiro
S
Miura
Issei
I
Komuro
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002460:Cell Line; D003584:Cytological Techniques / Q000379:methods; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D054314:Drug Inverse Agonism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011869:Radioligand Assay / Q000379:methods; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D013314:Stress, Mechanical; D015533:Transcriptional Activation; D014162:Transfection / Q000379:methods
D008024:Ligands; D016760:Proto-Oncogene Proteins c-fos; D044140:Receptor, Angiotensin, Type 1; D048049:Extracellular Signal-Regulated MAP Kinases