Protein kinase A regulates AKAP250 (gravin) scaffold binding to the β2-adrenergic receptor

被引:87
作者
Tao, JC
Wang, HY
Malbon, CC [1 ]
机构
[1] SUNY Stony Brook, Hlth Sci Ctr, Dept Pharmacol, Stony Brook, NY 11794 USA
[2] SUNY Stony Brook, Hlth Sci Ctr, Dept Physiol & Biophys, Stony Brook, NY 11794 USA
关键词
beta-adrenergic receptor; AKAP; gravin; protein kinase A; protein kinase C; scaffold;
D O I
10.1093/emboj/cdg628
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A-kinase-anchoring protein 250 (AKAP250; gravin) acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. The receptor-binding domain of the scaffold and the regulation of the receptor-scaffold association was revealed through mutagenesis and biochemical analyses. The AKAP domain found in other members of this superfamily is essential for the scaffold-receptor interactions. Gravin constructs lacking the AKAP domain displayed no binding to the receptor. Metabolic labeling studies in vivo demonstrate agonist-stimulated phosphorylation of gravin and enhanced gravin-receptor association. Analysis of the AKAP domain revealed two canonical PKA sites phosphorylated in response to elevated cAMP, blocked by PKA inhibitor, and essential for scaffold-receptor association and for resensitization of the receptor. The AKAP appears to provide the catalytic PKA activity responsible for phosphorylation of the scaffold in response to agonist activation of the receptor as well as for the association of the scaffold with the receptor, a step critical to receptor resensitization.
引用
收藏
页码:6419 / 6429
页数:11
相关论文
共 19 条