mu-Opioid receptors desensitize less rapidly than delta-opioid receptors due to less efficient activation of arrestin.

Lowe JD, Celver JP, Gurevich VV, Chavkin C
J Biol Chem. 2002 277 (18): 15729-35

PMID: 11861651 · DOI:10.1074/jbc.M200612200

Receptor desensitization by G-protein receptor kinases (GRK) and arrestins is likely to be an important component underlying the development of tolerance to opioid drugs. Reconstitution of this process in Xenopus oocytes revealed distinct differences in the kinetics of GRK and arrestin regulation of the closely related opioid receptors mu (MOR), delta (DOR), and kappa (KOR). We demonstrated that under identical conditions, GRK and arrestin-dependent desensitization of MOR proceeds dramatically slower than that of DOR. Furthermore, GRK3 phosphorylation sites required for opioid receptor desensitization also greatly differ. The determinants for DOR and KOR desensitization reside in the carboxyl-terminal tail, whereas MOR depends on Thr-180 in the second intracellular loop. Although this later finding might indicate an inefficient phosphorylation of MOR Thr-180, increasing the amount of arrestin expressed greatly increased the rate of MOR desensitization to a rate comparable with that of DOR. Similarly, coexpression of a constitutively active arrestin 2(R169E) with MOR and DOR desensitized both receptors in an agonist-dependent, GRK-independent manner at rates that were indistinguishable. Together, these data suggest that it is the activation of arrestin, rather than its binding, that is the rate-limiting step in MOR desensitization. In addition, mutation of Thr-161 in DOR, homologous to MOR Thr-180, significantly inhibited the faster desensitization of DOR. These results suggest that DOR desensitization involves phosphorylation of both the carboxyl-terminal tail and the second intracellular loop that together leads to a more efficient activation of arrestin and thus faster desensitization.

MeSH Terms (24)

Amino Acid Sequence Amino Acid Substitution Animals Arrestin Arrestins Cloning, Molecular Enkephalin, Ala(2)-MePhe(4)-Gly(5)- Enkephalin, D-Penicillamine (2,5)- G-Protein-Coupled Receptor Kinase 3 GTP-Binding Proteins Kinetics Mice Models, Molecular Mutagenesis, Site-Directed Oocytes Phosphoproteins Phosphorylation Protein-Serine-Threonine Kinases Protein Conformation Receptors, Opioid, delta Receptors, Opioid, mu Recombinant Proteins Threonine Xenopus laevis

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