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NeuroMolecular Medicine

, Volume 16, Issue 2, pp 499–509 | Cite as

C-terminus of Human BKca Channel Alpha Subunit Enhances the Permeability of the Brain Endothelial Cells by Interacting with Caveolin-1 and Triggering Caveolin-1 Intracellular Trafficking

  • Yang Song
  • Ping Wang
  • Jun Ma
  • Yixue XueEmail author
Original Paper

Abstract

The blood–tumor barrier (BTB) significantly limits the delivery of chemotherapeutic drugs to brain tumors. In this study, we found a significant increase in the permeability of BTB by mediating the association of the C-terminus of alpha subunit of human large-conductance calcium-activated potassium channels (hSlo1c) with caveolin-1 (Cav-1). We present evidence for the first time that hSlo1c associates with Cav-1 in human brain microvascular endothelial cells (HBMECs). A 57-amino acid (966–1022) fragment in hSlo1c was identified to be critical for hSlo1c/Cav-1 interaction. Activation of HBMECs transfected with fusion plasmids of pCMV–hSlo1c containing aa966–1022 by NS1619 selectively enhanced BTB permeability in a BTB model from the co-culture of HBMECs and U87 MG cells but not if the fusion plasmid lacks this fragment. This effect was attenuated by filipin, an agent disrupting caveolae or deletion of the potential interaction fragment, suggesting hSlo1c/Cav-1 association is crucial for regulating the permeability of BTB. Furthermore, we found that hSlo1c/Cav-1 association boosted Cav-1 transferring from the cell membrane to the cytoplasm of HBMECs. Our study indicates that cytoplasmic hSlo1c not only associates with Cav-1 but also has functional consequences on the permeability of BTB by triggering the intracellular trafficking of its interacting protein partner, Cav-1.

Keywords

BKca HSlo1 Caveolin-1 Blood–tumor barrier HBMECs 

Notes

Acknowledgments

This work is supported by Grants from the Natural Science Foundation of China (81001029, 81171131, 81172197, 81272564, 81272795, 81100893), the special fund for Scientific Research of Doctor-degree Subjects in Colleges and Universities, (20102104110009), the Natural Science Foundation of Liaoning Province in China (No. 201102300), Liaoning Science and Technology Plan Projects (No. 2011225020), and Shenyang Science and Technology Plan Projects (Nos. F11-264-1-15 and F12-277-1-05).

Conflict of interest

The authors declare no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  1. 1.Department of Neurobiology, College of Basic MedicineChina Medical UniversityShenyangPeople’s Republic of China
  2. 2.Department of Experimental Center of the Functional Subjects, College of Basic MedicineChina Medical UniversityShenyangPeople’s Republic of China
  3. 3.Institute of Pathology and Pathophysiology, College of Basic MedicineChina Medical UniversityShenyangPeople’s Republic of China

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