PT  - JOURNAL ARTICLE
AU  - Just, Sascha
AU  - Illing, Susann
AU  - Trester-Zedlitz, Michelle
AU  - Lau, Elaine K.
AU  - Kotowski, Sarah J.
AU  - Miess, Elke
AU  - Mann, Anika
AU  - Doll, Christian
AU  - Trinidad, Jonathan C.
AU  - Burlingame, Alma L.
AU  - von Zastrow, Mark
AU  - Schulz, Stefan
TI  - Differentiation of Opioid Drug Effects by Hierarchical Multi-Site Phosphorylation
AID  - 10.1124/mol.112.082875
DP  - 2013 Mar 01
TA  - Molecular Pharmacology
PG  - 633--639
VI  - 83
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/83/3/633.short
4100  - http://molpharm.aspetjournals.org/content/83/3/633.full
SO  - Mol Pharmacol2013 Mar 01; 83
AB  - Differences in the ability of opioid drugs to promote regulated endocytosis of μ-opioid receptors are related to their tendency to produce drug tolerance and dependence. Here we show that drug-specific differences in receptor internalization are determined by a conserved, 10-residue sequence in the receptor’s carboxyl-terminal cytoplasmic tail. Diverse opioids induce receptor phosphorylation at serine (S)375, present in the middle of this sequence, but opioids differ markedly in their ability to drive higher-order phosphorylation on flanking residues [threonine (T)370, T376, and T379]. Multi-phosphorylation is required for the endocytosis-promoting activity of this sequence and occurs both sequentially and hierarchically, with S375 representing the initiating site. Higher-order phosphorylation involving T370, T376, and T379 specifically requires GRK2/3 isoforms, and the same sequence controls opioid receptor internalization in neurons. These results reveal a biochemical mechanism differentiating the endocytic activity of opioid drugs.