PT  - JOURNAL ARTICLE
AU  - Yi-Ting Chiu
AU  - Chongguang Chen
AU  - Daohai Yu
AU  - Stefan Schulz
AU  - Lee-Yuan Liu-Chen
TI  - Agonist-Dependent and -Independent κ Opioid Receptor Phosphorylation: Distinct Phosphorylation Patterns and Different Cellular Outcomes
AID  - 10.1124/mol.117.108555
DP  - 2017 Nov 01
TA  - Molecular Pharmacology
PG  - 588--600
VI  - 92
IP  - 5
4099  - http://molpharm.aspetjournals.org/content/92/5/588.short
4100  - http://molpharm.aspetjournals.org/content/92/5/588.full
SO  - Mol Pharmacol2017 Nov 01; 92
AB  - We reported previously that the selective agonist U50,488H promoted phosphorylation of the mouse κ opioid receptor (KOPR) at residues S356, T357, T363, and S369. Here, we found that agonist (U50,488H)-dependent KOPR phosphorylation at all the residues was mediated by Gi/oα proteins and multiple protein kinases [GRK2, GRK3, GRK5, GRK6 and protein kinase C (PKC)]. In addition, PKC activation by phorbol ester induced agonist-independent KOPR phosphorylation. Compared with U50,488H, PKC activation promoted much higher S356/T357 phosphorylation, much lower T363 phosphorylation, and similar levels of S369 phosphorylation. After U50,488H treatment, GRKs, but not PKC, were involved in agonist-induced KOPR internalization. In contrast, PKC activation caused a lower level of agonist-independent KOPR internalization, compared with U50,488H. U50,488H-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2) was G protein-, but not β-arrestin-, dependent. After U50,488H treatment, GRK-mediated, but not PKC-mediated, KOPR phosphorylation followed by β-arrestin recruitment desensitized U50,488H-induced ERK1/2 response. Therefore, agonist-dependent (GRK- and PKC-mediated) and agonist-independent (PKC-promoted) KOPR phosphorylations show distinct phosphorylation patterns, leading to diverse cellular outcomes.