Pumping Ca²⁺ up H⁺ gradients: a Ca²⁺–H⁺ exchanger without a membrane

Cellular processes are exquisitely sensitive to H+ and Ca2+ ions because of powerful ionic interactions with proteins. By regulating the spatial and temporal distribution of intracellular [Ca2+] and [H+], cells such as cardiac myocytes can exercise control over their biological function. A well-established paradigm in cellular physiology is that ion concentrations are regulated by specialized, membrane-embedded transporter proteins. Many of these couple the movement of two or more ionic species per transport cycle, thereby linking ion concentrations among neighbouring compartments. Here, we compare and contrast canonical membrane transport with a novel type of Ca(2+)-H+ coupling within cytoplasm, which produces uphill Ca2+ transport energized by spatial H+ ion gradients, and can result in the cytoplasmic compartmentalization of Ca2+ without requiring a partitioning membrane. The mechanism, demonstrated in mammalian myocytes, relies on diffusible cytoplasmic buffers, such as carnosine, homocarnosine and ATP, to which Ca2+ and H+ ions bind in an apparently competitive manner. These buffer molecules can actively recruit Ca2+ to acidic microdomains, in exchange for the movement of H+ ions. The resulting Ca2+ microdomains thus have the potential to regulate function locally. Spatial cytoplasmic Ca(2+)-H+ exchange (cCHX) acts like a 'pump' without a membrane and may be operational in many cell types.