Functional antagonism of different G protein-coupled receptor kinases for β-arrestin-mediated angiotensin II receptor signaling

被引:273
作者
Kim, J
Ahn, S
Ren, XR
Whalen, EJ
Reiter, E
Wei, HJ
Lefkowitz, RJ [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA
[2] Duke Univ, Med Ctr, Dept Biochem, Durham, NC 27710 USA
[3] Duke Univ, Med Ctr, Howard Hughes Med Inst, Durham, NC 27710 USA
关键词
angiotensin receptor; extracellular signal-regulated kinase phosphorylation; small interfering RNA;
D O I
10.1073/pnas.0409532102
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
beta-arrestins bind to G protein-coupled receptor kinase (GRK)-phosphorylated seven transmembrane receptors, desensitizing their activation of G proteins, while concurrently mediating receptor endocytosis, and some aspects of receptor signaling. We have used RNA interference to assess the roles of the four widely expressed isoforms of GRKs (GRK 2, 3, 5, and 6) in regulating beta-arrestin-mediated signaling to the mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK) 1/2 by the angiotensin II type 1A receptor. Angiotensin II-stimulated receptor phosphorylation, beta-arrestin recruitment, and receptor endocytosis are all mediated primarily by GRK2/3. In contrast, inhibiting GRK 5 or 6 expression abolishes beta-arrestin-mediated ERK activation, whereas lowering GRK 2 or 3 leads to an increase in this signaling. Consistent with these findings, beta-arrestin-mediated ERK activation is enhanced by overexpression of GRK 5 and 6, and reciprocally diminished by GRK 2 and 3. These findings indicate distinct functional capabilities of beta-arrestins bound to receptors phosphorylated by different classes of GRKs.
引用
收藏
页码:1442 / 1447
页数:6
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