Clark R B, Friedman J, Dixon R A, Strader C D
Graduate School of Biomedical Sciences, University of Texas Health Science Center, Houston 77225.
Mol Pharmacol. 1989 Sep;36(3):343-8.
The molecular basis for heterologous desensitization of the beta-adrenergic receptor (beta AR) was investigated by site-directed mutagenesis of the beta AR protein. Rapid heterologous desensitization of agonist-stimulated adenylyl cyclase activity was observed when L cells expressing the wild-type beta AR were incubated with 50 nM epinephrine. This desensitization response could be mimicked in a cell-free system by incubation with cAMP-dependent protein kinase (cA.PK). Deletion of amino acid residues 259-262 from the beta AR, removing one of the two consensus sequences in the receptor for phosphorylation by cA.PK, abolished the ability of the receptor to undergo rapid heterologous desensitization. In contrast, deletion of the other cA.PK consensus sequence (residues 343-348) or truncation of the Ser/Thr-rich C-terminal tail of the beta AR (deletion of residues 354-418) did not affect this heterologous desensitization process. These results suggest that the action of cA.PK on amino acid residue(s) contained within the sequence 259-262 of the beta AR is required for rapid heterologous desensitization of the receptor in response to agonists.
通过对β-肾上腺素能受体（βAR）蛋白进行定点诱变，研究了βAR异源脱敏的分子基础。当用50 nM肾上腺素孵育表达野生型βAR的L细胞时，观察到激动剂刺激的腺苷酸环化酶活性快速异源脱敏。在无细胞系统中，通过与cAMP依赖性蛋白激酶（cA.PK）孵育可模拟这种脱敏反应。从βAR中缺失氨基酸残基259 - 262，去除了受体中cA.PK磷酸化的两个共有序列之一，消除了受体进行快速异源脱敏的能力。相反，缺失另一个cA.PK共有序列（残基343 - 348）或截断βAR富含Ser/Thr的C末端尾巴（缺失残基354 - 418）并不影响这种异源脱敏过程。这些结果表明，cA.PK对βAR序列259 - 262内所含氨基酸残基的作用是受体对激动剂快速异源脱敏所必需的。
