Flies without scramblases (right) have extra synaptic vesicles.

Flies lacking both scramblase genes show normal phospholipid distribution and scrambling in response to physiological stimuli, report Acharya et al. on page 69. The mutant animals, however, have increased synaptic vesicle activity at the neuromuscular junction, leading the team to hypothesize that scramblases may modulate secretory activity.

Scramblases were initially identified in human blood cells through a search for proteins that could transfer phospholipids from one membrane leaflet to the other. Yet mice lacking two of the four mouse scramblase genes showed normal phospholipid scrambling. Therefore, either the other two homologues compensated for scrambling function or the protein family has a previously unidentified function.

To find out, Acharya et al. generated flies lacking both of the Drosophila scramblase genes. During apoptosis, phosphatidylserine moved from the inner leaflet to the outer one as expected, indicating that the scrambling function remained intact in cells lacking either or both scramblases. Scrambling was also normal during phagocytosis in bacteria-infected animals.

The double-mutant flies were, however, jumpy in their vials, a phenotype previously associated with synaptic function defects. When the team examined the structure and function of the neuromuscular junction, they found an excess of both synaptic vesicles trafficking and neurotransmitter release, relative to wild type. This is consistent with previous studies linking scramblase proteins to modulation of secretory pathways.