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Detachment of surface membrane invagination systems by cationic amphiphilic drugs

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posted on 21.01.2016, 10:47 by Sangar Osman, Kirk A. Taylor, Natalie Allcock, Richard D. Rainbow, Martyn P. Mahaut-Smith
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.

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Citation

Scientific Reports, 2016, 6, 18536

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cardiovascular Sciences

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VoR (Version of Record)

Published in

Scientific Reports

Publisher

Nature Publishing Group

eissn

2045-2322

Acceptance date

19/11/2015

Copyright date

2016

Available date

21/01/2016

Publisher version

http://www.nature.com/articles/srep18536

Language

en

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