SummaryDistinct 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 -opioid receptor (OR) determines the different abilities of the OR agonists DPDPE and TIPP to activate ERK by G-protein-or -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 -arrestin1/2-mediated pathway. Moreover, we found that DPDPE gained the capacity to adopt the -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 -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.

Aquatic or riparian vegetation strongly affects sediment transport in rivers, whose processes affect the relationship between nature and humanity (Västilä & Järvelä, 2018). Accordingly, national strategies or regulations from nations, such as the Ecological protection and high-quality development of the Yellow River (mother river) Basin,

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