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Received for publication January 10, 2006.
Revised April 16, 2006.
Accepted for publication May 5, 2006.
The ability of two opioid agonists, DAMGO and morphine, to induce µ-opioid receptor (MOR) phosphorylation, desensitization and internalization was examined in HEK293 cells expressing rat MOR1 as well GIRK channel subunits. Both DAMGO and morphine activated GIRK currents but the maximum response to DAMGO was greater than that of morphine indicating that morphine is a partial agonist. The responses to DAMGO and morphine desensitized rapidly in the presence of either drug. Expression of a dominant negative mutant G protein-coupled receptor kinase 2 (GRK2), GRK2-K220R, markedly attenuated the DAMGO-induced desensitization of MOR1, but had no effect on morphine-induced MOR1 desensitization. In contrast, inhibition of PKC either by the PKC inhibitory peptide, PKC (19-31) or staurosporine reduced MOR1 desensitization by morphine, but not that induced by DAMGO. Morphine and DAMGO enhanced MOR1 phosphorylation over basal. The PKC inhibitor GF109203X inhibited MOR1 phosphorylation under basal conditions and in the presence of morphine, but did not inhibit DAMGO-induced phosphorylation. DAMGO induced arrestin-2 translocation to the plasma membrane and considerable MOR1 internalization whereas morphine did not induce arrestin-2 translocation and induced very little MOR1 internalization. Thus DAMGO and morphine each induce desensitization of MOR1 signalling in HEK293 cells but by different molecular mechanisms; DAMGO-induced desensitization is GRK2-dependent whereas morphine-induced desensitization is PKC-dependent. MORs desensitised by DAMGO activation are then readily internalised by an arrestin-dependent mechanism whereas those desensitised by morphine are not. These data suggest that opioid agonists induce different conformations of the MOR that are susceptible to different desensitizing and internalization processes.
Key words:
Opioid, Gi family, Protein Kinase C, G protein regulation, Desensitization/uncoupling, GRKs, barrestins, Drug tolerance/dependence, Opioids
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