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首页> 外文期刊>American Journal of Physiology >Phosphorylation of GRK2 by PKA augments GRK2-mediated phosphorylation, internalization, and desensitization of VPAC2 receptors in smooth muscle
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Phosphorylation of GRK2 by PKA augments GRK2-mediated phosphorylation, internalization, and desensitization of VPAC2 receptors in smooth muscle

机译：PKA对GRK2的磷酸化增强了GRK2介导的平滑肌VPAC2受体的磷酸化，内在化和脱敏

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First published December 12,2007; doi:10.1152/ajpcell.00229.2007.-The smooth muscle of the gut expresses mainly Gs protein-coupled vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide receptors (VPAC2 receptors), which belong to the secretin family of G protein-coupled receptors. The extent to which PKA and G protein-coupled receptor kinases (GRKs) participate in homologous desensitization varies greatly among the secretin family of receptors. The present study identified the novel role of PKA in homologous desensitization of VPAC2 receptors via the phosphorylation of GRK2 at Ser685. VEP induced phosphorylation of GRK2 in a concentration-dependent fashion, and the phosphorylation was abolished by blockade of PKA with cell-permeable myristoylated protein kinase inhibitor (PKI) or in cells expressing PKA phosphorylation-site deficient GRK2(S685A). Phosphorylation of GRK2 increased its activity and binding to Gbeta. VTP-induced phosphorylation of VPAC2 receptors was abolishedin muscle cells expressing kinase-deficient GRK2(K220R) and attenuated in cells expressing GRK2(S685A) or by PKI. VPAC2 receptor internalization (determined from residual 125I-labeled VIP binding and receptor biotinylation after a 30-min exposure to V3P) was blocked in cells expressing GRK2(K220R) and attenuated in cells expressing GRK2(S685A) or by PKI. Finally, VPAC2 receptor degradation (determined from residual 125I-labeled VEP binding and receptor expression after a prolonged exposure to VIP) and functional VPAC2 receptor desensitization (determined from the decrease in adenylyl cyclase activity and cAMP formation after a 30-min exposure to VIP) were abolished in cells expressing GRK2(K220R) and attenuated in cells expressing GRK2(S685A). These results demonstrate that in gastric smooth muscle VPAC2 receptor phosphorylation is mediated by GRK2. Phosphorylation of GRK2 by PKA enhances GRK2 activity and its ability to induce VPAC2 receptor phosphorylation, internalization, desensitization, and degradation.
机译：首次发布时间：2007年12月12日; doi：10.1152 / ajpcell.00229.2007.-肠道平滑肌主要表达Gs蛋白偶联的血管活性肠肽（VIP）/垂体腺苷酸环化酶激活肽受体（VPAC2受体），属于G蛋白的促分泌素家族-耦合受体。 PKA和G蛋白偶联受体激酶（GRK）参与同源脱敏的程度在受体的促分泌素家族之间差异很大。本研究通过在Ser685处GRK2的磷酸化确定了PKA在VPAC2受体同源脱敏中的新作用。 VEP以浓度依赖的方式诱导GRK2的磷酸化，磷酸化被细胞渗透性肉豆蔻酰化蛋白激酶抑制剂（PKI）阻断PKA或在表达PKA磷酸化位点缺陷的GRK2（S685A）的细胞中被取消。 GRK2的磷酸化增加了它的活性和与Gbeta的结合。 VTP诱导的VPAC2受体的磷酸化在表达激酶缺陷型GRK2（K220R）的肌肉细胞中被消除，在表达GRK2（S685A）的细胞中或通过PKI减弱。在表达GRK2（K220R）的细胞中，VPAC2受体的内在化作用（由残留的125I标记的VIP结合和受体生物素化作用决定）在表达GRK2（K220R）的细胞中被阻断，在表达GRK2（S685A）的细胞中或通过PKI减弱。最后，VPAC2受体降解（取决于长时间暴露于VIP后残留的125I标记的VEP结合和受体表达）和功能性VPAC2受体脱敏（取决于暴露于VIP 30分钟后腺苷酸环化酶活性的下降和cAMP的形成）在表达GRK2（K220R）的细胞中被消除，而在表达GRK2（S685A）的细胞中被减弱。这些结果表明，在胃平滑肌中，VPAC2受体的磷酸化是由GRK2介导的。 PKA使GRK2磷酸化可增强GRK2活性，并增强其诱导VPAC2受体磷酸化，内在化，脱敏和降解的能力。

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