Sodium-calcium exchanger

The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, NCX, or exchange protein) is an antiporter membrane protein which removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na+) by allowing Na+ to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca2+). The NCX removes a single calcium ion in exchange for the import of three sodium ions. The exchanger exists in many different cell types and animal species. The NCX is considered one of the most important cellular mechanisms for removing Ca2+.

The exchanger is usually found in the plasma membranes and the membranes of endoplasmic reticulum of excitable cells.

Function
The Na+/Ca2+ exchanger does not bind very tightly to Ca2+ (has a low affinity), but it can transport the ions rapidly (has a high capacity), transporting up to five thousand Ca2+ ions per second. Therefore it requires large concentrations of Ca2+ to be effective, but is useful for ridding the cell of large amounts of Ca2+ in a short time, as is needed in a neuron after an action potential. Thus the exchanger also likely plays an important role in regaining the cell's normal calcium concentrations after an excitotoxic insult. Another, more ubiquitous transmembrane pump that exports calcium from the cell is the Plasma membrane Ca2+ ATPase (PMCA), which has a much higher affinity but a much lower capacity. Since the PMCA is capable of effectively binding to Ca2+ even when its concentrations are quite low, it is better suited to the task of maintaining the very low concentrations of calcium that are normally within a cell. Therefore the activities of the NCX and the PMCA complement each other.

The exchanger is involved in a variety of cell functions including the following:
 * control of neurosecretion
 * activity of photoreceptor cells
 * cardiac muscle relaxation
 * maintenance of Ca2+ concentration in the sarcoplasmic reticulum in cardiac cells
 * maintenance of Ca2+ concentration in the endoplasmic reticulum of both excitable and nonexcitable cells
 * excitation-contraction coupling

Reversibility
Since the transport is electrogenic (alters the membrane potential), depolarization of the membrane can reverse the exchanger's direction if the cell is depolarized enough, as may occur in excitotoxicity. In addition, like other transport proteins, the amount and direction of transport depends on transmembrane substrate gradients. This fact can be protective because increases in intracellular Ca2+ concentration that occur in excitotoxicity may activate the exchanger in the forward direction even in the presence of a lowered extracellular Na+ concentration. However, it also means that when intracellular levels of Na+ rise beyond a critical point, the NCX begins importing Ca2+  The NCX may operate in both forward and reverse directions simultaneously in different areas of the cell, depending on the combined effects of Na+ and Ca2+ gradients.

History
In 1968, H Reuter and N Sinz published findings that when Na+ is removed from the medium surrounding a cell, the efflux of Ca2+ is inhibited, and they proposed that there might be a mechanism for exchanging the two ions. In 1969, a group led by PF Baker that was experimenting using squid axons published a finding that there existed a means of Na+ exit from cells other than the sodium-potassium pump.