title: Activation of ERM-family proteins via RhoA-ROCK signaling increases intestinal P-gp expression and leads to attenuation of oral morphine analgesia.
abstract: Previously, we reported that repeated oral treatment with etoposide (ETP) causes attenuation of oral morphine analgesia through upregulation of ileal P-glycoprotein (P-gp) mediated by Ras homolog gene family, member A (RhoA) activation. However, the detailed mechanism of the increase in ileal P-gp via RhoA activation remains unknown. Recently, it has been reported that ezrin-radixin-moesin (ERM) proteins, linking several plasma-membrane proteins to the actin cytoskeleton, are involved in the membrane localization and functional activity of P-gp. Moreover, the cross-linking activities of ERM are known to be regulated by RhoA and Rho-associated coiled-coil containing kinase (ROCK). Here, we examined the involvement of ERM in the changes in expression of P-gp via RhoA and ROCK in ileal membrane induced by ETP. Repeated oral treatment with ETP significantly increased the ileal membrane localization of ERM and phosphorylated ERM (p-ERM) in association with upregulation of P-gp and activation of RhoA and ROCK. Interestingly, coadministration of rosuvastatin (inhibitor of RhoA activation) and fasudil (ROCK inhibitor) prevented increments in the activation and phosphorylation of ERM, respectively. In conclusion, upregulation of ileal membrane localization of ERM and p-ERM via activation of RhoA/ROCK induced by ETP treatment may be involved in the regulation of ileal membrane localization of P-gp.
authors.affiliation: Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe 650-8586, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Kobori
authors.forename: Shinichi
authors.initials: S
authors.lastname: Harada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nakamoto
authors.forename: Shogo
authors.initials: S
authors.lastname: Tokuyama
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D000698:Analgesia; D000701:Analgesics, Opioid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000378:metabolism; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology / Q000627:therapeutic use*; D005464:Fluorobenzenes / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007082:Ileum / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008840:Microfilament Proteins / Q000032:analysis / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D054460:rho-Associated Kinases / Q000032:analysis / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000032:analysis / Q000378:metabolism*; D000099149:Ezrin
chemical_list: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000701:Analgesics, Opioid; D000972:Antineoplastic Agents, Phytogenic; D003598:Cytoskeletal Proteins; D005047:Etoposide; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008565:Membrane Proteins; D008840:Microfilament Proteins; D009020:Morphine; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000099149:Ezrin; C071058:moesin; C071776:radixin; C049347:fasudil