Activation of ERM-family proteins via RhoAROCK signaling increases intestinal P-gp expression and leads to attenuation of oral morphine analgesia

作者：Kobori Takuro; Harada Shinichi; Nakamoto Kazuo; Tokuyama Shogo^*

来源：Journal of Pharmaceutical Sciences, 2013, 102(3): 1095-1105.

DOI：10.1002/jps.23441

• ABC transporters
• P-glycoprotein
• efflux pumpus
• membrane translocation
• drug interactions
• intestinal epithelia
• ileum

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 ezrinradixinmoesin (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.

• 出版日期2013-3