%0 Journal Article %1 Sanni:2010:Br-J-Pharmacol:20718747 %A Sanni, S J %A Hansen, J T %A Bonde, M M %A Speerschneider, T %A Christensen, G L %A Munk, S %A Gammeltoft, S %A Hansen, J L %D 2010 %J Br J Pharmacol %K beta-Arrestin high-affinity receptor-fusion-protein %N 1 %P 150-161 %R 10.1111/j.1476-5381.2010.00875.x %T beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations %U http://www.ncbi.nlm.nih.gov/pubmed/20718747 %V 161 %X The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often induces higher binding affinity for agonists. Here, we examined interactions between AT(1A) receptors and beta-arrestins to look for differences between the AT(1A) receptor interaction with beta-arrestin1 and beta-arrestin2.Ligand-induced interaction between AT(1A) receptors and beta-arrestins was measured by Bioluminescence Resonance Energy Transfer 2. AT(1A)-beta-arrestin1 and AT(1A)-beta-arrestin2 fusion proteins were cloned and tested for differences using immunocytochemistry, inositol phosphate hydrolysis and competition radioligand binding.Bioluminescence Resonance Energy Transfer 2 analysis showed that beta-arrestin1 and 2 were recruited to AT(1A) receptors with similar ligand potencies and efficacies. The AT(1A)-beta-arrestin fusion proteins showed attenuated G protein signalling and increased agonist binding affinity, while antagonist affinity was unchanged. Importantly, larger agonist affinity shifts were observed for AT(1A)-beta-arrestin2 than for AT(1A)-beta-arrestin1.beta-Arrestin1 and 2 are recruited to AT(1A) receptors with similar ligand pharmacology and stabilize AT(1A) receptors in distinct high-affinity conformations. However, beta-arrestin2 induces a receptor conformation with a higher agonist-binding affinity than beta-arrestin1. Thus, this study demonstrates that beta-arrestins interact with AT(1A) receptors in different ways and suggest that AT(1) receptor biased agonists with the ability to recruit either of the beta-arrestins selectively, would be possible to design.

@article{Sanni:2010:Br-J-Pharmacol:20718747, abstract = {The angiotensin II type 1 (AT(1)) receptor belongs to family A of 7 transmembrane (7TM) receptors. The receptor has important roles in the cardiovascular system and is commonly used as a drug target in cardiovascular diseases. Interaction of 7TM receptors with G proteins or beta-arrestins often induces higher binding affinity for agonists. Here, we examined interactions between AT(1A) receptors and beta-arrestins to look for differences between the AT(1A) receptor interaction with beta-arrestin1 and beta-arrestin2.Ligand-induced interaction between AT(1A) receptors and beta-arrestins was measured by Bioluminescence Resonance Energy Transfer 2. AT(1A)-beta-arrestin1 and AT(1A)-beta-arrestin2 fusion proteins were cloned and tested for differences using immunocytochemistry, inositol phosphate hydrolysis and competition radioligand binding.Bioluminescence Resonance Energy Transfer 2 analysis showed that beta-arrestin1 and 2 were recruited to AT(1A) receptors with similar ligand potencies and efficacies. The AT(1A)-beta-arrestin fusion proteins showed attenuated G protein signalling and increased agonist binding affinity, while antagonist affinity was unchanged. Importantly, larger agonist affinity shifts were observed for AT(1A)-beta-arrestin2 than for AT(1A)-beta-arrestin1.beta-Arrestin1 and 2 are recruited to AT(1A) receptors with similar ligand pharmacology and stabilize AT(1A) receptors in distinct high-affinity conformations. However, beta-arrestin2 induces a receptor conformation with a higher agonist-binding affinity than beta-arrestin1. Thus, this study demonstrates that beta-arrestins interact with AT(1A) receptors in different ways and suggest that AT(1) receptor biased agonists with the ability to recruit either of the beta-arrestins selectively, would be possible to design.}, added-at = {2013-07-24T10:17:01.000+0200}, author = {Sanni, S J and Hansen, J T and Bonde, M M and Speerschneider, T and Christensen, G L and Munk, S and Gammeltoft, S and Hansen, J L}, biburl = {https://www.bibsonomy.org/bibtex/298cda1251142530712fcffa1ae5c1225/madmicha}, description = {beta-Arrestin 1 and 2 stabilize the angiotens... [Br J Pharmacol. 2010] - PubMed - NCBI}, doi = {10.1111/j.1476-5381.2010.00875.x}, interhash = {794811837b3b5cd7b6e1b37d098c0d63}, intrahash = {98cda1251142530712fcffa1ae5c1225}, journal = {Br J Pharmacol}, keywords = {beta-Arrestin high-affinity receptor-fusion-protein}, month = sep, number = 1, pages = {150-161}, pmid = {20718747}, timestamp = {2013-08-26T08:26:21.000+0200}, title = {beta-Arrestin 1 and 2 stabilize the angiotensin II type I receptor in distinct high-affinity conformations}, url = {http://www.ncbi.nlm.nih.gov/pubmed/20718747}, volume = 161, year = 2010 }