Protein kinase Czeta mediates micro-opioid receptor-induced cross-desensitization of chemokine receptor CCR5.

ABSTRACT: We have previously shown that the ?-opioid receptor (MOR) is capable of mediating cross-desensitization of several chemokine receptors including CCR5, but the biochemical mechanism of this process has not been fully elucidated. We have carried out a series of functional and biochemical studies and found that the mechanism of MOR-induced cross-desensitization of CCR5 involves the activation of PKC?. Inhibition of PKC? by its pseudosubstrate inhibitor, or its siRNA, or dominant negative mutants suppresses the cross-desensitization of CCR5. Our results further indicate that the activation of PKC? is mediated through a pathway involving phosphoinositol-dependent kinase-1 (PDK1). In addition, activation of MOR elevates the phosphorylation level and kinase activity of PKC?. The phosphorylation of PKC? can be suppressed by a dominant negative mutant of PDK1. We observed that following MOR activation, the interaction between PKC? and PDK1 is immediately increased based on the analysis of fluorescent resonance energy transfer in cells with the expression of PKC?-YFP and PDK1-CFP. In addition, cells expressing PKC? kinase motif mutants (Lys-281, Thr-410, Thr-560) fail to exhibit full MOR-induced desensitization of CCR5 activity. Taken together, we propose that upon DAMGO treatment, MOR activates PKC? through a PDK1-dependent signaling pathway to induce CCR5 phosphorylation and desensitization. Because CCR5 is a highly proinflammatory receptor, and a critical coreceptor for HIV-1, these results may provide a novel approach for the development of specific therapeutic agents to treat patients with certain inflammatory diseases or AIDS.

SUBMITTER: Song C 

PROVIDER: S-EPMC3121462 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature