Calcium is unique among metals because its ions have a very large concentration gradient across the plasma membrane of all cells, from 10(-3) M Ca2+ outside, to 10(-7) M Ca2+ inside. This gradient is maintained by the use of metabolic energy through ion pumping, and its existence allows cells to use transient increases in the intracellular Ca2+ concentration as signals, which regulate cell function. In neurones these Ca signals are initiated by electrical activity (action potentials) which open voltage-dependent Ca channels in the plasma membrane, allowing Ca to enter the cell. Intracellular Ca signals can also be produced by transmitters at synapses, which open Ca channels, either directly, or indirectly by causing local depolarization and the opening of voltage-dependent Ca channels. The main effects of Ca signals on neurones are to alter their electrical activity, by modifying the opening and closing of Na and K channels, and to stimulate the release of transmitter substance. Ca has a host of other effects, such as the regulation of metabolic activity, the regulation of cell growth, and the long-term modification of synaptic efficiency, and it is even implicated in the destruction of neurones.