The taming of a scramblase

Eukaryotic cells are separated from their environment by a 30-A-thick delimitation of lipid and protein ˚ —the plasma membrane (PM). Although a greater measure of affection has historically been garnered by their protein machines, cells have devoted ∼5% of their genes to building lipids. In this pursuit of lipidic diversity, cells have developed repertoires of thousands of lipid species (van Meer et al., 2008), many of which fall into the category of phospholipids (PLs), which are largely responsible for the PM’s bilayer arrangement. The PLs within the PM bilayer are actively arranged in an asymmetric orientation rendering the exofacial surface largely composed of cylindrical species (e.g., phosphatidylcholine), while the cytofacial leaflet retains most conical and charged species (e.g., phosphatidylethanolamine and phosphatidylserine [PS]). Despite this organization, many of our cells maintain the ability to rapidly abolish PM lipid asymmetry, exposing cytofacial PLs to the exofacial surface as a means of coordinating intercellular processes (Bevers and Williamson, 2016). Bevers et al. (1982) first described this PL “scrambling” in platelet activation, where PS exposure on the exofacial surface propagates coagulation. A few years after Bevers’ description, several others noted that platelet activation was accompanied by a rapid alkalization of intracellular pH (pHi), and that blocking this alkalization inhibited PS exposure (Bucki et al., 2006; Zavoico et al., 1986). In an earlier issue of the Journal of General Physiology, Liang and Yang (2021) show us why. In fact, these platelets, and likely other cells that use nonapoptotic scrambling as a signaling module, have tamed their scramblases to fit a distinct biological niche via pHi.