C-Terminal Membrane Association of Bestrophin 3 and Its Activation as a Chloride Channel

C-Terminal Membrane Association of Bestrophin 3 and Its Activation as a Chloride Channel Bestrophin 3 (Best3), a member of the bestrophin Cl− channel family, is a candidate of cGMP-sensitive, Ca2+-activated Cl− channel in vascular smooth muscle cells. The Best3 channel was recently found to play an important role in vasomotion. However, the mechanism for its activation has not been clarified. In previous studies, we found that a Best3 C-terminal sequence (amino acids 353–404) was associated with the cellular membrane. The sequence includes an autoinhibitory domain (356IPSFLGS362) and a downstream basic residue domain (amino acids 384–397). In this study, we found that the sequence (368–383) between the two domains is actually a determinant for Best3 C-terminal membrane associability. Deletion of the sequence almost abolished the membrane association but did not activate the Best3 channel. Treatment of Best3-expressing HEK293 cells with the PI3Kα inhibitor IV (a Best3 activator) could not abolish but weakened the Best3 membrane association. The result supports the assumption that the positively charged basic residues in the Best3 C terminus are likely associated with the membranous negatively charged phospholipids, which plays a role in the regulation of Best3 activation. But the relationship between membrane associability and Best3 activation seems more complicated than expected. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Membrane Biology Springer Journals

C-Terminal Membrane Association of Bestrophin 3 and Its Activation as a Chloride Channel

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Publisher
Springer-Verlag
Copyright
Copyright © 2012 by Springer Science+Business Media New York
Subject
Life Sciences; Biochemistry, general; Human Physiology
ISSN
0022-2631
eISSN
1432-1424
D.O.I.
10.1007/s00232-012-9514-7
Publisher site
See Article on Publisher Site

Abstract

Bestrophin 3 (Best3), a member of the bestrophin Cl− channel family, is a candidate of cGMP-sensitive, Ca2+-activated Cl− channel in vascular smooth muscle cells. The Best3 channel was recently found to play an important role in vasomotion. However, the mechanism for its activation has not been clarified. In previous studies, we found that a Best3 C-terminal sequence (amino acids 353–404) was associated with the cellular membrane. The sequence includes an autoinhibitory domain (356IPSFLGS362) and a downstream basic residue domain (amino acids 384–397). In this study, we found that the sequence (368–383) between the two domains is actually a determinant for Best3 C-terminal membrane associability. Deletion of the sequence almost abolished the membrane association but did not activate the Best3 channel. Treatment of Best3-expressing HEK293 cells with the PI3Kα inhibitor IV (a Best3 activator) could not abolish but weakened the Best3 membrane association. The result supports the assumption that the positively charged basic residues in the Best3 C terminus are likely associated with the membranous negatively charged phospholipids, which plays a role in the regulation of Best3 activation. But the relationship between membrane associability and Best3 activation seems more complicated than expected.

Journal

The Journal of Membrane BiologySpringer Journals

Published: Nov 3, 2012

References

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