Manifold active-state conformations in GPCRs: agonist-activated constitutively active mutant AT1 receptor preferentially couples to Gq compared to the wild-type AT1 receptor |
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Authors: | Lee ChangWoo Hwang Si Ae Jang Sei-Heon Chung Hye-Shin Bhat Manjunatha B Karnik Sadashiva S |
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Affiliation: | Department of Molecular Cardiology, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA. leec@daegu.ac.kr |
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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. |
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Keywords: | Angiotensin II receptor G protein β-Arrestin |
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