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Serine 363 of the δ-opioid receptor is crucial for adopting distinct pathways to activate ERK1/2 in response to stimulation with different ligands
Chi Xu, Min-Hua Hong, Le-Sha Zhang, Yuan-Yuan Hou, Yu-Hua Wang, Fei-Fei Wang, Yue-Jun Chen, Xue-Jun Xu, Jie Chen, Xin Xie, Lan Ma, Zhi-Qiang Chi, Jing-Gen Liu


Distinct opioid receptor agonists have been proved to induce differential patterns of ERK activation, but the underlying mechanisms remain unclear. Here, we report that Ser363 in the δ-opioid receptor (δOR) determines the different abilities of the δOR agonists DPDPE and TIPP to activate ERK by G-protein- or β-arrestin-dependent pathways. Although both DPDPE and TIPP activated ERK1/2, they showed different temporal, spatial and desensitization patterns of ERK activation. We show that that DPDPE employed G protein as the primary mediator to activate the ERK cascade in an Src-dependent manner, whereas TIPP mainly adopted a β-arrestin1/2-mediated pathway. Moreover, we found that DPDPE gained the capacity to adopt the β-arrestin1/2-mediated pathway upon Ser363 mutation, accompanied by the same pattern of ERK activation as that induced by TIPP. Additionally, we found that TIPP- but not DPDPE-activated ERK could phosphorylate G-protein-coupled receptor kinase-2 and β-arrestin1. However, such functional differences of ERK disappeared with the mutation of Ser363. Therefore, the present study reveals a crucial role for Ser363 in agonist-specific regulation of ERK activation patterns and functions.

  • Accepted August 26, 2010.
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