There are a multitude of transport systems that contribute to the regulation of the internal Ca²⁺ ion concentration (Figure 1). The Ca-ATPase pump is found in the cell membrane and several organelle membranes. It actively pumps Ca²⁺ ions out of the cell or into intracellular organelles (mitochondria and endoplasmic reticulum), where the Ca²⁺ ions are sequestered. In addition, there is the Na-Ca exchanger that uses the energy of the Na⁺ ion gradient to transport Ca²⁺ ions out of the cell. Calcium binding proteins are another important part of the system. These proteins bind Ca²⁺ ions and act like buffers, rapidly reducing free Ca²⁺ ion concentrations following an influx of Ca²⁺ ions through open calcium channels. These buffers give the more slowly acting pump and transporters some time to remove the ions from the intracellular fluid. The buffers limit the duration and extent of the change in free Ca²⁺ ion concentration within the cell.

Figure 1 Summary of the various systems for handling Ca²⁺ ions within the cell.

Ca²⁺ Ions as Second Messengers

Perhaps oddly, given the effort that cells expend to keep internal Ca²⁺ ion concentrations low, Ca²⁺ ions have an important role as intracellular signaling molecules. Although an apparently unlikely candidate, given the simple nature of these molecules, Ca²⁺ ions modulate the function of a myriad of proteins and cellular functions. The ions can bind directly to proteins to regulate their function, examples include synaptotagmin and the calcium-activated potassium channels. Alternatively, they can work by binding to an intermediary protein, typically calmodulin, that then binds to and modifies the function of the regulated protein. Through these two mechanisms changes in intracellular Ca²⁺ ion concentrations can trigger or modulate a wide variety of cellular functions.

Typically, increases in Ca²⁺ ion concentrations are triggered by the opening of Ca²⁺ channels, either in the cell membrane or in the membranes of the organelles that sequester Ca²⁺ ions. These calcium fluxes produce a transient increase in the free calcium ion concentration in the cell that triggers downstream cell signaling pathways. This signaling system is used by all cells but is particularly important for electrically excitable cells because it provides a means of converting an electrical signal into a biochemical one. Examples of important cellular functions dependent on Ca²⁺ signaling include synaptic transmission and muscle contraction.

Internal Ca²⁺ Concentration and Cell Death

Maintenance of a low intracellular Ca²⁺ ion concentration is critical for normal cell function. In most cells, a prolonged increase in intracellular Ca²⁺ ion concentration rapidly leads to cell death.

Blockade of blood flow (and thus oxygen) in the brain or the heart quickly leads to ischemic tissue damage in these organs. The brain and the heart are very metabolically active tissues and as a consequence use up their local energy supplies very quickly. This makes them particularly vulnerable to ischemic tissue damage because the maintenance of low Ca²⁺ ion concentrations inside the cell is strongly dependent on maintained cellular energy levels. The decrease in local oxygen tension during ischemia results in a rapid fall in the energy available from ATP hydrolysis, which leads to a rise in calcium levels. The rise in intracellular calcium levels can trigger cellular processes that lead to the destruction of the cell.