title: Detachment of surface membrane invagination systems by cationic amphiphilic drugs.
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.
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester, UK, LE1 9HN.
authors.forename: Sangar
authors.initials: S
authors.lastname: Osman
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester, UK, LE1 9HN.
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Taylor
authors.affiliation: Centre for Core Biotechnology Services, University of Leicester, Leicester, UK, LE1 9HN.
authors.forename: Natalie
authors.initials: N
authors.lastname: Allcock
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Leicester, UK, LE1 9HN.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Rainbow
authors.affiliation: Department of Molecular and Cell Biology, University of Leicester, Leicester, UK, LE1 9HN.
authors.forename: Martyn P
authors.initials: MP
authors.lastname: Mahaut-Smith
mesh_terms: D000818:Animals; D022081:Cell Surface Extensions / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004963:Estrenes / Q000494:pharmacology*; D008297:Male; D008533:Megakaryocytes / Q000502:physiology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000502:physiology / Q000648:ultrastructure; D010640:Phenothiazines / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D017208:Rats, Wistar; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D004963:Estrenes; D010640:Phenothiazines; D011760:Pyrrolidinones; D013449:Sulfonamides; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C074854:U 73343; C017967:W 7