Contribution of Radixin to P-Glycoprotein Expression and Transport Activity in Mouse Small Intestine In Vivo

Yano, Kentarô; Tomono, Takumi; Sakai, Riyo; Kano, Takashi; Morimoto, Kaori; Kato, Yukio; Ogihara, Takuo

doi:10.1002/jps.23637

Cited by 28 publications

(45 citation statements)

References 39 publications

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“…the levels radixin but not ezrin or moesin bound to P-gp in the ileal membrane fraction were both dramatically increased in mice treated with oral ETP compared with those treated with the vehicle alone. These results are consistent with just recent finding that the plasma membrane localization and functional activity of P-gp in the small intestinal were dramatically reduced in mice lacking radixin 32) and that knockdown of radixin in Caco-2 cell lines, derived from human intestinal epithelium, markedly decreases the plasma membrane localization of P-gp, 18) indicating that radxin plays a critical role in modulating the protein expression of P-gp in the small intestine. In addition, our present results provide further evidence that among the three ERM proteins, radixin has, at least in part, impact on the protein expression level of P-gp in the small intestinal membrane.…”

Section: Discussionsupporting

confidence: 92%

“…12,29) In recent years, some researchers have proposed that radixin functions as a scaffold protein for P-gp and other membrane transporters not only in the canalicular membrane of the hepatocytes, 14,20) but also in the small intestine, similarly to ezrin. 18,29,32) To give a specific example, the knockdown of radixin dramatically decreases the plasma membrane localization of P-gp in association with a decrease in its drug efflux activity in the hepatocytes, compared with the more moderate effect of ezrin or moesin knockdown. 20) Similarly, a deficiency or disturbed localization of radixin in the liver causes a marked decreases in the canalicular membrane localization of MRP2, 17) suggesting that radixin works as a scaffold protein for MRP2.…”

Section: Discussionmentioning

confidence: 99%

“…12) Ezrin is expressed in the epithelium, 12,18,29) and is the only ERM protein that has been proven to interact with P-gp by use of immunoprecipitation analysis. 28) On the other hand, radixin is expressed in the liver 14,17,20,31) and kidney, 29) as well as in the epithelium of the small intestine, 32) although not to the extent of ezrin. 18,29) Furthermore, radixin has been just recently proposed to play a crucial role in regulating the membrane localization and functional activity of P-gp in the small intestinal by using mice lacking radixin.…”

mentioning

confidence: 99%

“…18,29) Furthermore, radixin has been just recently proposed to play a crucial role in regulating the membrane localization and functional activity of P-gp in the small intestinal by using mice lacking radixin. 32) Since the small intestinal P-gp acts as a first barrier against the absorption of various substrate drugs administered via the oral route, [33][34][35][36][37][38] it seems to be important to accumulate the evidence with regard to the regulatory factors for the plasma membrane localization of P-gp. However, there has been no direct evidence investigating the molecular interaction between P-gp and radixin in the small intestine and the role of radixin in the alteration mechanism of P-gp.…”

mentioning

confidence: 99%

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Radixin Influences the Changes in the Small Intestinal P-Glycoprotein by Etoposide Treatment

Kobori

Harada

Nakamoto

et al. 2013

Biological & Pharmaceutical Bulletin

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Previously, we reported that repeated oral administration of etoposide (ETP) increases P-glycoprotein (P-gp) expression in association with activation of ezrin/radixin/moesin (ERM) in the small intestine. Radixin has recently attracted attention for its critical role in the plasma membrane localization of certain drug transporters including P-gp by working as a scaffold protein. However, there have been no report investigating that radixin really interacts with small intestinal P-gp and is involved in the mechanism by which the levels of P-gp are altered. Here, we examined whether radixin is involved in the increased P-gp expression in the small intestine after ETP treatment. Repeated oral treatment with ETP (10 mg/kg/day) for 7 d significantly increased ERM proteins bound to P-gp in the small intestine as determined by immunoprecipitation analysis. In particular, radixin but not ezrin or moesin bound to P-gp was dramatically increased in association with the up-regulation of P-gp in the small intestinal membrane, and radixin was highly colocalized with P-gp as measured by immunofluorescence analysis. In conclusion, radixin may contribute, at least in part, to an increase in the expression of the small intestinal P-gp upon induction with repeated oral treatment with ETP.Key words P-glycoprotein; radixin; small intestine; ATP-binding cassette transporterThe expression levels and functional activity of plasma membrane proteins are not necessarily dependent upon their mRNA levels, as exemplified by P-glycoprotein (P-gp). 1,2)While various transcriptional factors have been identified as key regulators of P-gp mRNA levels, 3) little is known about the post-transcriptional regulation of this protein.We have focused our previous studies on ezrin, radixin and moesin, all of which are involved to some degree in the post-transcriptional regulation of P-gp. 4) Ezrin was originally identified as a component of microvilli from chicken intestinal brush borders. 5) Radixin was isolated from rat liver as a component of the adherens junctions, 6) while moesin was characterized as a heparin-binding protein from smooth muscle cells in the bovine uterus. 7,8) These three proteins are closely related with ∼75% amino-acid sequence homology, and together they comprise the ezrin, radixin and moesin (ERM) family.9) The high sequence homology of these proteins makes them difficult to distinguish from each other unless specific antibodies against each individual ERM member are used. Thus, ezrin, radixin and moesin have been considered as the ERM family as a whole in the majority of previous reports. The ERM play several critical roles in tissue morphology and organization as well as in cell motility, 5,[10][11][12][13][14] by acting alone as a cross linker between the plasma membrane and the actin cytoskeleton. 5,15,16) Recently, ERM have attracted much attention as scaffold proteins regulating the plasma membrane localization and functional activities of several drug transporters including P-gp. 4,15,17,18) In fact, ERM have already been...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Radixin Influences the Changes in the Small Intestinal P-Glycoprotein by Etoposide Treatment

Kobori

Harada

Nakamoto

et al. 2013

Biological & Pharmaceutical Bulletin

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“…We found that in mouse small intestine, P-gp mRNA and protein expression levels tend to increase from the upper region to the lower region. 44) In addition, Rdx protein expression shows a similar trend. However, P-gp protein expression in plasma membrane fractions of Rdx KO mice was decreased in the middle and lower parts of the small intestine and the segmental variation was lost.…”

Section: )mentioning

confidence: 83%

Advances in Studies of P-Glycoprotein and Its Expression Regulators

Yano

Tomono

Ogihara

2018

Biological & Pharmaceutical Bulletin

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This review deals with recent advances in studies on P-glycoprotein (P-gp) and its expression regulators, focusing especially on our own research. Firstly, we describe findings demonstrating that the distribution of P-gp along the small intestine is heterogeneous, which explains why orally administered P-gp substrate drugs often show bimodal changes of plasma concentration. Secondly, we discuss the post-translational regulation of P-gp localization and function by the scaffold proteins ezrin, radixin and moesin (ERM proteins), together with recent reports indicating that tissue-specific differences in regulation by ERM proteins in normal tissues might be retained in corresponding cancerous tissues. Thirdly, we review evidence that P-gp activity is enhanced in the process of epithelial-to-mesenchymal transition (EMT), which is associated with cancer progression, without any increase in expression of P-gp mRNA. Finally, we describe two examples in which P-gp critically influences the brain distribution of drugs, i.e., oseltamivir, where low levels of P-gp associated with early development allow oseltamivir to enter the brain, potentially resulting in neuropsychiatric side effects in children, and cilnidipine, where impairment of P-gp function in ischemia allows cilnidipine to enter the ischemic brain, where it exerts a neuroprotective action.

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Involvement of PtdIns(4,5)P2 in the Regulatory Mechanism of Small Intestinal P-Glycoprotein Expression

Kobori

Harada

Nakamoto

et al. 2014

Journal of Pharmaceutical Sciences

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Contribution of Radixin to P-Glycoprotein Expression and Transport Activity in Mouse Small Intestine In Vivo

Cited by 28 publications

References 39 publications

Radixin Influences the Changes in the Small Intestinal P-Glycoprotein by Etoposide Treatment

Radixin Influences the Changes in the Small Intestinal P-Glycoprotein by Etoposide Treatment

Advances in Studies of P-Glycoprotein and Its Expression Regulators

Involvement of PtdIns(4,5)P2 in the Regulatory Mechanism of Small Intestinal P-Glycoprotein Expression

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