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The sodium-calcium exchanger (often denoted Na<sup>+</sup>/Ca<sup>2+</sup> exchanger, NCX, or exchange protein) is an antiporter ion pump membrane protein which removes calcium from cells. It uses the energy that is stored in the electrochemical gradient of sodium (Na<sup>+</sup>) by allowing Na<sup>+</sup> to flow down its gradient across the plasma membrane in exchange for the countertransport of calcium ions (Ca<sup>2+</sup>). The NCX removes a single calcium ion in exchange for the import of three sodium ions.[1] using the Na<sup>+</sup>
The Na<sup>+</sup>/Ca<sup>2+</sup> exchanger does not bind very tightly to Ca<sup>2+</sup> (has a low affinity), but it can transport the ions rapidly (has a high capacity), transporting up to five thousand Ca2+ ions per second.[2] Therefore it requires large concentrations of Ca<sup>2+</sup> to be effective, but is useful for ridding the cell of large amounts of Ca<sup>2+</sup> 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 Ca<sup>2+</sup> 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.[3] Therefore the activities of the NCX and the PMCA complement each other.
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.[1] In addition, like other transport proteins, the amount and direction of transport depends on transmembrane substrate gradients.[1] This fact can be protective because increases in intracellular Ca<sup>2+</sup> concentration that occur in excitotoxicity may activate the exchanger in the forward direction even in the presence of a lowered extracellular Na<sup>+</sup> concentration.[1] However, it also means that when intracellular levels of Na<sup>+</sup> rise beyond a critical point, the NCX begins importing Ca<sup>2+</sup>[1][4][5] The NCX may operate in both forward and reverse directions simultaneously in different areas of the cell, depending on the combined effects of Na<sup>+</sup> and Ca<sup>2+</sup> gradients.[1]