The exocytotic release of hormones and neurotransmitters from subcellular storage vesicles begins with the elevation of cytosolic calcium concentration and ends with the storage vesicle open to the cell exterior through fusion of the vesicle membrane with the plasma membrane. No one step in the intervening process is understood at the molecular level. The function, if not the intention, of this report will be to focus attention on how little we know about the role of the membrane lipids in the fusion of the two membranes.

The fusion of two membranes requires an extreme reordering of the opposing lipid bilayers, very likely through intermediate formation on micelle-like structures. During reordering, lipids in the cytoplasmic monolayers which first make contact would form spherical inverted micelles with polar head groups in the centers of the spheres. Fatty acid chains would be in contact with neighboring spheres and with the fatty acid chains of the more distant monolayers of the two membranes. Evidence for the existence of such inverted micelles was developed through the study of artificial lipid bilayers. It was found that some phospholipids form only bilayers but that others are more likely to form the “hexagonal phase 11” composed of inverted micellar structures as proposed for the membrane fusion intermediate. Phosphatidyl ethanolamine and phosphatidyl serine alone tend to form the hexagonal phase rather than bilayers, and cholesterol also favors reordering of the bilayer.‘The process of fusion is also expected to be favored by a high degree of membrane fluidity, which is determined largely by the content of unsaturated fatty acids. The steric irregularity of the chain which is caused by double bonds lowers van der Waals contacts and reduces cohesion of the lipid phase. The presence in a membrane of lysolecithin (or other lysolipids) will cause dislocations in the lipid array and add a relatively hydrophilic element to the lipid phase. Addition of lysolecithin to a suspension of cells or lipid vesicles can promote fusion between them? Free fatty acids too, if present in a membrane, should tend to induce rearrangement of membrane structure-after all, at physiological pH they are soap.