Considering the intrinsically asymmetric nature of plasma membranes, with mostly zwitterionic lipids on the outer lealet and abundant negatively charged lipids on the inner lealet, it may be reasonable to think that evolution has made the outer surface of cells more inert to external cation distribution in order to maintain a stable shape, while the inner surface of cells is more sensitive to Ca 2+ for responding to internal signaling. In addition, by inluencing the mechanical properties of membranes, Ca 2+ may also regulate membrane-bound proteins, especially mechanosensitive proteins. For example, mechanosensitive ion channels are involved in many physiological processes, such as touch, hearing, balance, and the sensation of pain, which can be activated by forces exerted on membranes and the resulting surface tension, imbalanced stress, and membrane curvature.