Breaking asymmetry: phospholipid scrambling by GPCRs and TMEM16 proteins (351.2)

Abstract

Polar lipids must flip rapidly, and often bidirectionally, across membranes to support cellular life. For example, phospholipids are synthesized on the cytoplasmic face of the endoplasmic reticulum (ER) and must be apportioned between the luminal and cytoplasmic leaflets for uniform expansion of the ER during cell growth. Transbilayer movement of lipids is also needed for the generation, maintenance and dissipation of transbilayer lipid asymmetry at the plasma membrane. As flipping is energetically costly, specialized transporters increase its intrinsically low rate to a physiologically relevant level. While some of these transporters couple ATP hydrolysis to lipid movement, many function without any discernible metabolic energy input. The molecular identification of these latter ‘ATP‐independent flippases’, also termed ‘scramblases’, has eluded researchers for decades. We now report the first examples of this novel class of proteins: rhodopsin, a prototypical G protein‐coupled receptor, is a constitutively active, ATP‐independent phospholipid flippase (Menon et al. (2011) Curr. Biol. 21: 149), and afTMEM16, a fungal homolog of the TMEM16 family of ion channels is a Ca2+‐dependent phospholipid scramblase (Malvezzi et al. (2013) Nature Commun. 4: 2367). Both proteins break transbilayer lipid asymmetry.