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- Publisher Website: 10.1073/pnas.1111414108
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- PMID: 22106313
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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)
Title | 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) | ||||||||||
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Authors | |||||||||||
Keywords | Basal ectoplasmic specialization Male contraception Seminiferous epithelial cycle | ||||||||||
Issue Date | 2011 | ||||||||||
Publisher | National 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? | ||||||||||
Abstract | The 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 Identifier | http://hdl.handle.net/10722/146035 | ||||||||||
ISSN | 2023 Impact Factor: 9.4 2023 SCImago Journal Rankings: 3.737 | ||||||||||
PubMed Central ID | |||||||||||
ISI Accession Number ID |
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 Field | Value | Language |
---|---|---|
dc.contributor.author | Su, L | en_HK |
dc.contributor.author | Mruk, DD | en_HK |
dc.contributor.author | Lui, WY | en_HK |
dc.contributor.author | Lee, WM | en_HK |
dc.contributor.author | Chen, CY | en_HK |
dc.date.accessioned | 2012-03-27T09:07:32Z | - |
dc.date.available | 2012-03-27T09:07:32Z | - |
dc.date.issued | 2011 | en_HK |
dc.identifier.citation | Proceedings Of The National Academy Of Sciences Of The United States Of America, 2011, v. 108 n. 49, p. 19623-19628 | en_HK |
dc.identifier.issn | 0027-8424 | en_HK |
dc.identifier.uri | http://hdl.handle.net/10722/146035 | - |
dc.description.abstract | The 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.language | eng | en_US |
dc.publisher | National Academy of Sciences. The Journal's web site is located at http://www.pnas.org | en_HK |
dc.relation.ispartof | Proceedings of the National Academy of Sciences of the United States of America | en_HK |
dc.subject | Basal ectoplasmic specialization | en_HK |
dc.subject | Male contraception | en_HK |
dc.subject | Seminiferous epithelial cycle | en_HK |
dc.subject.mesh | Blood-Testis Barrier - drug effects - metabolism | - |
dc.subject.mesh | Focal Adhesion Protein-Tyrosine Kinases - metabolism | - |
dc.subject.mesh | Membrane Proteins - metabolism | - |
dc.subject.mesh | P-Glycoproteins - genetics - metabolism | - |
dc.subject.mesh | Phosphoproteins - metabolism | - |
dc.title | 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) | en_HK |
dc.type | Article | en_HK |
dc.identifier.email | Lui, WY: wylui@hku.hk | en_HK |
dc.identifier.email | Lee, WM: hrszlwm@hku.hk | en_HK |
dc.identifier.authority | Lui, WY=rp00756 | en_HK |
dc.identifier.authority | Lee, WM=rp00728 | en_HK |
dc.description.nature | link_to_OA_fulltext | en_US |
dc.identifier.doi | 10.1073/pnas.1111414108 | en_HK |
dc.identifier.pmid | 22106313 | - |
dc.identifier.pmcid | PMC3241815 | - |
dc.identifier.scopus | eid_2-s2.0-83755207358 | en_HK |
dc.identifier.hkuros | 198854 | en_US |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-83755207358&selection=ref&src=s&origin=recordpage | en_HK |
dc.identifier.volume | 108 | en_HK |
dc.identifier.issue | 49 | en_HK |
dc.identifier.spage | 19623 | en_HK |
dc.identifier.epage | 19628 | en_HK |
dc.identifier.eissn | 1091-6490 | - |
dc.identifier.isi | WOS:000297683800043 | - |
dc.publisher.place | United States | en_HK |
dc.identifier.scopusauthorid | Su, L=34871019700 | en_HK |
dc.identifier.scopusauthorid | Mruk, DD=6701823934 | en_HK |
dc.identifier.scopusauthorid | Lui, WY=35220192400 | en_HK |
dc.identifier.scopusauthorid | Lee, WM=24799156600 | en_HK |
dc.identifier.scopusauthorid | Chen, CY=54784137800 | en_HK |
dc.identifier.issnl | 0027-8424 | - |