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Article: P-glycoprotein regulates blood-testis barrier dynamics via its effects on the occludin/zonula occludens 1 (ZO-1) protein complex mediated by focal adhesion kinase (FAK)

TitleP-glycoprotein regulates blood-testis barrier dynamics via its effects on the occludin/zonula occludens 1 (ZO-1) protein complex mediated by focal adhesion kinase (FAK)
Authors
KeywordsBasal ectoplasmic specialization
Male contraception
Seminiferous epithelial cycle
Issue Date2011
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 49, p. 19623-19628 How to Cite?
AbstractThe blood-testis barrier (BTB), one of the tightest blood-tissue barriers in the mammalian body, creates an immune-privileged site for postmeiotic spermatid development to avoid the production of antibodies against spermatid-specific antigens, many of which express transiently during spermiogenesis and spermiation. However, the BTB undergoes extensive restructuring at stage VIII of the epithelial cycle to facilitate the transit of preleptotene spermatocytes and to prepare for meiosis. This action thus prompted us to investigate whether this stage can be a physiological window for the delivery of therapeutic and/or contraceptive drugs across the BTB to exert their effects at the immune-privileged site. Herein, we report findings that P-glycoprotein, an ATP-dependent efflux drug transporter and an integrated component of the occludin/zonula occludens 1 (ZO-1) adhesion complex at the BTB, structurally interacted with focal adhesion kinase (FAK), creating the occludin/ZO-1/FAK/P-glycoprotein regulatory complex. Interestingly, a knockdown of P-glycoprotein by RNAi was found to impede Sertoli cell BTB function, making the tight junction (TJ) barrier "leaky." This effect was mediated by changes in the protein phosphorylation status of occludin via the action of FAK, thereby affecting the endocytic vesicle-mediated protein trafficking events that destabilized the TJ barrier. However, the silencing of P-glycoprotein, although capable of impeding drug transport across the BTB and TJ permeability barrier function, was not able to induce the BTB to be "freely" permeable to adjudin. These findings indicate that P-glycoprotein is involved in BTB restructuring during spermatogenesis but that P-glycoprotein-mediated restructuring does not "open up" the BTB to make it freely permeable to drugs.
Persistent Identifierhttp://hdl.handle.net/10722/146035
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
National Institute of Child Health and Human Development, National Institutes of HealthR01 HD056034
R01 HD056034-02-S1
U54 HD029990
CRCG Small Project Funding
University of Hong Kong
Hong Kong Research Grants CouncilHKU772009
HKU773710
Funding Information:

This work was supported in part by National Institute of Child Health and Human Development, National Institutes of Health Grants R01 HD056034 and R01 HD056034-02-S1 (to C.Y.C.) and U54 HD029990 Project 5 (to C.Y.C.), CRCG Small Project Funding, University of Hong Kong (to W.M.L.), Hong Kong Research Grants Council Grants HKU772009 and HKU773710 (to W.-Y.L.), and University of Hong Kong Postgraduate Research Award (to L.S.).

References

 

DC FieldValueLanguage
dc.contributor.authorSu, Len_HK
dc.contributor.authorMruk, DDen_HK
dc.contributor.authorLui, WYen_HK
dc.contributor.authorLee, WMen_HK
dc.contributor.authorChen, CYen_HK
dc.date.accessioned2012-03-27T09:07:32Z-
dc.date.available2012-03-27T09:07:32Z-
dc.date.issued2011en_HK
dc.identifier.citationProceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 49, p. 19623-19628en_HK
dc.identifier.issn0027-8424en_HK
dc.identifier.urihttp://hdl.handle.net/10722/146035-
dc.description.abstractThe blood-testis barrier (BTB), one of the tightest blood-tissue barriers in the mammalian body, creates an immune-privileged site for postmeiotic spermatid development to avoid the production of antibodies against spermatid-specific antigens, many of which express transiently during spermiogenesis and spermiation. However, the BTB undergoes extensive restructuring at stage VIII of the epithelial cycle to facilitate the transit of preleptotene spermatocytes and to prepare for meiosis. This action thus prompted us to investigate whether this stage can be a physiological window for the delivery of therapeutic and/or contraceptive drugs across the BTB to exert their effects at the immune-privileged site. Herein, we report findings that P-glycoprotein, an ATP-dependent efflux drug transporter and an integrated component of the occludin/zonula occludens 1 (ZO-1) adhesion complex at the BTB, structurally interacted with focal adhesion kinase (FAK), creating the occludin/ZO-1/FAK/P-glycoprotein regulatory complex. Interestingly, a knockdown of P-glycoprotein by RNAi was found to impede Sertoli cell BTB function, making the tight junction (TJ) barrier "leaky." This effect was mediated by changes in the protein phosphorylation status of occludin via the action of FAK, thereby affecting the endocytic vesicle-mediated protein trafficking events that destabilized the TJ barrier. However, the silencing of P-glycoprotein, although capable of impeding drug transport across the BTB and TJ permeability barrier function, was not able to induce the BTB to be "freely" permeable to adjudin. These findings indicate that P-glycoprotein is involved in BTB restructuring during spermatogenesis but that P-glycoprotein-mediated restructuring does not "open up" the BTB to make it freely permeable to drugs.en_HK
dc.languageengen_US
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.orgen_HK
dc.relation.ispartofProceedings of the National Academy of Sciences of the United States of Americaen_HK
dc.subjectBasal ectoplasmic specializationen_HK
dc.subjectMale contraceptionen_HK
dc.subjectSeminiferous epithelial cycleen_HK
dc.subject.meshBlood-Testis Barrier - drug effects - metabolism-
dc.subject.meshFocal Adhesion Protein-Tyrosine Kinases - metabolism-
dc.subject.meshMembrane Proteins - metabolism-
dc.subject.meshP-Glycoproteins - genetics - metabolism-
dc.subject.meshPhosphoproteins - metabolism-
dc.titleP-glycoprotein regulates blood-testis barrier dynamics via its effects on the occludin/zonula occludens 1 (ZO-1) protein complex mediated by focal adhesion kinase (FAK)en_HK
dc.typeArticleen_HK
dc.identifier.emailLui, WY: wylui@hku.hken_HK
dc.identifier.emailLee, WM: hrszlwm@hku.hken_HK
dc.identifier.authorityLui, WY=rp00756en_HK
dc.identifier.authorityLee, WM=rp00728en_HK
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1073/pnas.1111414108en_HK
dc.identifier.pmid22106313-
dc.identifier.pmcidPMC3241815-
dc.identifier.scopuseid_2-s2.0-83755207358en_HK
dc.identifier.hkuros198854en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-83755207358&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume108en_HK
dc.identifier.issue49en_HK
dc.identifier.spage19623en_HK
dc.identifier.epage19628en_HK
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:000297683800043-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridSu, L=34871019700en_HK
dc.identifier.scopusauthoridMruk, DD=6701823934en_HK
dc.identifier.scopusauthoridLui, WY=35220192400en_HK
dc.identifier.scopusauthoridLee, WM=24799156600en_HK
dc.identifier.scopusauthoridChen, CY=54784137800en_HK

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