title: Protein kinase Czeta mediates micro-opioid receptor-induced cross-desensitization of chemokine receptor CCR5.
abstract: We have previously shown that the μ-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 PKCζ. Inhibition of PKCζ 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 PKCζ is mediated through a pathway involving phosphoinositol-dependent kinase-1 (PDK1). In addition, activation of MOR elevates the phosphorylation level and kinase activity of PKCζ. The phosphorylation of PKCζ can be suppressed by a dominant negative mutant of PDK1. We observed that following MOR activation, the interaction between PKCζ and PDK1 is immediately increased based on the analysis of fluorescent resonance energy transfer in cells with the expression of PKCζ-YFP and PDK1-CFP. In addition, cells expressing PKCζ 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 PKCζ 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.
authors: Fels Institute for Cancer Research and Molecular Biology, Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA.
authors: Changcheng
authors: C
authors: Song
authors: Rahil T
authors: RT
authors: Rahim
authors: Penelope C
authors: PC
authors: Davey
authors: Filip
authors: F
authors: Bednar
authors: Giuseppe
authors: G
authors: Bardi
authors: Lily
authors: L
authors: Zhang
authors: Ning
authors: N
authors: Zhang
authors: Joost J
authors: JJ
authors: Oppenheim
authors: Thomas J
authors: TJ
authors: Rogers
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D015497:HIV-1; D006801:Humans; D051379:Mice; D009154:Mutation; D010446:Peptide Fragments; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019713:Receptors, CCR5; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D000099221:Protein Kinase C zeta
chemical_list: D000701:Analgesics, Opioid; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D010446:Peptide Fragments; D011493:Protein Kinase C; D017346:Protein Serine-Threonine Kinases; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D019713:Receptors, CCR5; D017450:Receptors, Opioid, mu; D000099221:Protein Kinase C zeta; C550179:CCR5 receptor (222-240); C000631429:PDK1 protein, human; C000631433:Pdk1 protein, mouse