PKA-mediated phosphorylation of the β1-adrenergic receptor promotes Gs/Gi switching
PKA-mediated phosphorylation of the β1-adrenergic receptor promotes Gs/Gi switching
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DOI：
10.1016/j.cellsig.2004.05.002
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发表时间：
2004-12-01
影响因子：
4.8
通讯作者：
Lefkowitz, RJ
中科院分区：
文献类型：
--
作者：
Martin, NP;Whalen, EJ;Lefkowitz, RJ
最近，研究表明，环AMP依赖性蛋白激酶（PKA）介导的β（2）-肾上腺素能受体（β（2）-AR）的磷酸化降低了其对G（s）的亲和力，并增加了其对G（i）的亲和力。在这里，我们证明，像β（2）-AR，β（1）-AR也能够“切换”其耦合从G（s）G（i）在PKA依赖性的方式。β（1）-AR能够通过G（s）激活腺苷酸环化酶，也可以激活细胞外调节激酶p44和p42（ERK 1/2）。在转染的CHO细胞中，观察到的β（1）-AR介导的ERK激活对百日咳毒素（PTX）敏感，表明G（i）/G（o）参与，对PKA抑制剂H-89敏感。PKA磷酸化位点突变为丙氨酸的β（1）-AR不能激活ERK。将这些相同的残基突变为天冬氨酸，模拟PKA磷酸化，导致G（s）刺激的cAMP积累减少和PTX敏感性ERK激活增加。这些结果有力地支持了β（1）-AR与β（2）-AR一样可以经历PKA依赖性“G（s）/G（i）转换”的假设。(C)2004年爱思唯尔公司All rights reserved.
Recently, it has been shown that PKA-mediated phosphorylation of the beta(2)-adrenergic receptor (beta(2)-AR) by the cyclic AMP-dependent protein kinase (PKA) reduces its affinity for G(s) and increases its affinity for G(i). Here we demonstrate that, like the beta(2)-AR, the beta(1)-AR is also capable of "switching" its coupling from G(s) to G(i) in a PKA-dependent manner. The beta(1)-AR is capable of activating adenylate cyclase via G(s), and can also activate the extracellular-regulated kinases, p44 and p42 (ERK1/2). In transfected CHO cells, the observed beta(1)-AR-mediated activation of ERK is both sensitive to pertussis toxin (PTX), indicating involvement of G(i)/G(o), and to the PKA inhibitor, H-89. beta(1)-ARs with PKA phosphorylation sites mutated to alanines are unable to activate ERK. Mutating these same residues to aspartic acid, mimicking PKA phosphorylation, leads to a decrease in G(s)-stimulated cAMP accumulation and an increase in PTX-sensitive ERK activation. These results strongly support the hypothesis that the beta(1)-AR, like the beta(2)-AR, can undergo PKA-dependent "G(s)/G(i) switching". (C) 2004 Elsevier Inc. All rights reserved.