Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/36344
Title: Detachment of surface membrane invagination systems by cationic amphiphilic drugs
Authors: Osman, Sangar
Taylor, Kirk A.
Allcock, Natalie
Rainbow, Richard D.
Mahaut-Smith, Martyn P.
First Published: 4-Jan-2016
Publisher: Nature Publishing Group
Citation: Scientific Reports, 2016, 6, 18536
Abstract: Several cell types develop extensive plasma membrane invaginations to serve a specific physiological function. For example, the megakaryocyte demarcation membrane system (DMS) provides a membrane reserve for platelet production and muscle transverse (T) tubules facilitate excitation:contraction coupling. Using impermeant fluorescent indicators, capacitance measurements and electron microscopy, we show that multiple cationic amphiphilic drugs (CADs) cause complete separation of the DMS from the surface membrane in rat megakaryocytes. This includes the calmodulin inhibitor W-7, the phospholipase-C inhibitor U73122, and anti-psychotic phenothiazines. CADs also caused loss of T tubules in rat cardiac ventricular myocytes and the open canalicular system of human platelets. Anionic amphiphiles, U73343 (a less electrophilic U73122 analogue) and a range of kinase inhibitors were without effect on the DMS. CADs are known to accumulate in the inner leaflet of the cell membrane where they bind to anionic lipids, especially PI(4,5)P2. We therefore propose that surface detachment of membrane invaginations results from an ability of CADs to interfere with PI(4,5)P2 interactions with cytoskeletal or BAR domain proteins. This establishes a detubulating action of a large class of pharmaceutical compounds.
DOI Link: 10.1038/srep18536
eISSN: 2045-2322
Links: http://www.nature.com/articles/srep18536
http://hdl.handle.net/2381/36344
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © 2016, the authors. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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