The electrostatic properties of the membrane interface are of paramount importance in numerous situations. Ca 2+ is particularly interesting in this respect due to its divalent nature. Although sharing common properties with other divalent cations, Ca 2+ is one of the most critical secondary messengers and functions by inducing ine-tuned electrostatic effects. For example, it was shown that blood clotting proteins associated with membrane surfaces become activated during the coagulation cascade, and Ca 2+ enhances protein penetration into the lipid monolayer and induces locculation of surface lipid aggregates. The high Ca 2+ levels inside presynaptic vesicles can prevent even the most lipophilic transmitters, such as dopamine from adhering to the inner lealet surface, thus rendering unhindered neurotransmitter release feasible. Ca 2+ also regulates the interactions between annexins and membranes, which may inluence cell membrane-related domain organization, endocytic, exocytic transport, and traficking. When Ca 2+ ions were pumped into cells by ion channels or transporters, they can generate large clusters by linking PIP 2 . In contrast, monovalent cations such as Na + and K + form smaller and less stable clusters. Moreover, a synergy exists between Ca 2+ and K + , facilitating the growth of PIP 2 clusters and the formation of more complex structures within the cell. Therefore, there have been extensive studies seeking to elucidate the effects of Ca 2+ on membrane properties.