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Interaction Between the µ Opioid Receptor and Filamin A Is Involved in Receptor Regulation and Trafficking

Departments of Psychiatry (I.O., M.L.A., H.K.K., N.A-T., J.M.H., E.J.S.) and Pharmacology (E.J.S.), New York University School of Medicine, New York, New York

The carboxyl tail of the human µ opioid receptor was shown to bind the carboxyl terminal region of human filamin A, a protein known to couple membrane proteins to actin. Results from yeast two-hybrid screening were confirmed by direct protein-protein binding and by coimmunoprecipitation of filamin and µ opioid receptor from cell lysates. To investigate the role of filamin A in opioid receptor function and regulation, we used the melanoma cell line M2, which does not express filamin A, and its subclone A7, transfected with human filamin A cDNA. Both cell lines were stably transfected with cDNA encoding myc-tagged human µ opioid receptor. Fluorescent studies, using confocal microscopy, provided evidence that filamin and µ opioid receptors were extensively colocalized on the membranes of filamin-expressing melanoma cells. The immunostaining of µ opioid receptors indicated that the lack of filamin had no detectable effect on membrane localization of the receptors. Moreover, µ opioid receptors function normally in the absence of filamin A, as evidenced by studies of opioid binding and DAMGO inhibition of forskolin-stimulated adenylyl cyclase. However, agonist-induced receptor down-regulation and functional desensitization were virtually abolished in cells lacking filamin A. The level of internalized µ-opioid receptors, after 30-min exposure to agonist, was greatly reduced, suggesting a role for filamin in µ opioid receptor trafficking. During these studies, we observed that forskolin activation of adenylyl cyclase was greatly reduced in filamin-lacking cells. An even more unexpected finding was the ability of long-term treatment with [D-Ala²,N-Me-Phe⁴,Gly⁵-ol]-enkephalin of M2 cells, containing µ opioid receptors, to restore normal forskolin activation. The mechanism of this effect is currently unknown. It is postulated that the observed effects on µ opioid receptor regulation by filamin A and, by implication, of the actin cytoskeleton may be the result of its role in µ opioid receptor trafficking.

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