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.