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J. Biol. Chem., Vol. 278, Issue 35, 33400-33407, August 29, 2003

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Selective Interactions between Helix VIII of the Human µ-Opioid Receptors and the C Terminus of Periplakin Disrupt G Protein Activation^*

Giu-Jie Feng, Elaine Kellett, Carol A. Scorer , Jonathan Wilde , Julia H. White  and Graeme Milligan ¶

From the Molecular Pharmacology Group, Division of Biochemistry and Molecular Biology, Institute of Biomedical and Life Sciences, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom, Pathway Discovery, Genomics and Proteomic Sciences, GlaxoSmithKline Medicines Research Centre, Stevenage SG1 2NY, United Kingdom, and the Psychiatry Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow CM19 5AW, United Kingdom

Analysis of interactions between the C-terminal tail of the MOP-1 and MOP-1A variants of the human µ-opioid receptor with proteins derived from a human brain cDNA library resulted in identification of the actin and intermediate filament-binding protein periplakin. Mapping of this interaction indicated that the predicted fourth intracellular loop/helix VIII of the receptor interacts with the C-terminal rod and linker region of periplakin. Periplakin is widely expressed in the central nervous system of both man and rat and demonstrated an overlapping but not identical distribution with µ-opioid (MOP) receptors. Co-expression of periplakin with MOP-1 or a MOP-1-eYFP fusion construct in HEK293 cells did not interfere with agonist-mediated internalization of the receptor. When co-expressed with a MOP-1-G_i1 fusion protein periplakin significantly reduced the capacity of the agonist to stimulate binding of ³⁵S-labeled guanosine 5'-3-O-(thio)triphosphate ([³⁵S]GTPS) to the receptor-associated G protein. By contrast, periplakin did not interfere with agonist-stimulation of [³⁵S]GTPS binding to either an _2A-adrenoreceptor-G_i1 fusion protein or a ₂-adrenoreceptor-G_s fusion protein, indicating its selectivity of function. This represents the first example of an opioid receptor-interacting protein that functions to disrupt agonist-mediated G protein activation.

Received for publication, June 4, 2003

^* The work was supported by the Biotechnology and Biosciences Research Council and the Medical Research Council. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Davidson Bldg., University of Glasgow, Glasgow G12 8QQ, Scotland, UK. Tel.: 44-141-330-5557; Fax: 44-141-330-4620; E-mail: g.milligan{at}bio.gla.ac.uk.

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