Cations induce shape remodeling of negatively charged phospholipid membranes.

The divalent cation Ca2+ is a key component in many cell signaling and membrane trafficking pathways. Ca2+ signal transduction commonly occurs through interaction with protein partners. However, in this study we show a novel mechanism by which Ca2+ may impact membrane structure. We find an asymmetric concentration of Ca2+ across the membrane triggers deformation of membranes containing negatively charged lipids such as phosphatidylserine (PS) and phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2 ). Membrane invaginations in vesicles were observed forming away from the leaflet with higher Ca2+ concentration, showing that Ca2+ induces negative curvature. We hypothesize that the negative curvature is produced by Ca2+ -induced clustering of PS and PI(4,5)P2 . In support of this notion, we find that Ca2+ -induced membrane deformation is stronger for membranes containing PI(4,5)P2 , which is known to more readily cluster in the presence of Ca2+ . The observed Ca2+ -induced membrane deformation is strongly influenced by Na+ ions. A high symmetric [Na+ ] across the membrane reduces Ca2+ binding by electrostatic shielding, inhibiting Ca2+ -induced membrane deformation. An asymmetric [Na+ ] across the membrane, however, can either oppose or support Ca2+ -induced deformation, depending on the direction of the gradient in [Na+ ]. At a sufficiently high asymmetric Na+ concentration it can impact membrane structure in the absence of Ca2+ . We propose that Ca2+ works in concert with curvature generating proteins to modulate membrane curvature and shape transitions. This novel structural impact of Ca2+ could be important for Ca2+ -dependent cellular processes that involve the creation of membrane curvature, including exocytosis, invadopodia, and cell motility.