The sodium-calcium exchanger (often denoted Na⁺/Ca²⁺ exchanger, NCX, or exchange protein) is an antiporter membrane protein that 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.^[1] The exchanger exists in many different cell types and animal species.^[2] The NCX is considered one of the most important cellular mechanisms for removing Ca²⁺.^[2]

The exchanger is usually found in the plasma membranes and the mitochondria and endoplasmic reticulum of excitable cells.^[3][4]

Function[edit]

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.^[5] 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.^[3] 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.^[6] 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:^[2]

• 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
• maintenance of low Ca²⁺ concentration in the mitochondria

The exchanger is also implicated in the cardiac electrical conduction abnormality known as delayed afterdepolarization.^[7] It is thought that intracellular accumulation of Ca²⁺ causes the activation of the Na⁺/Ca²⁺ exchanger. The result is a brief influx of a net positive charge (remember 3 Na⁺ in, 1 Ca²⁺ out), thereby causing cellular depolarization.^[7] This abnormal cellular depolarization can lead to a cardiac arrhythmia.

Reversibility[edit]

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, as with other transport proteins, the amount and direction of transport depends on transmembrane substrate gradients.^[1] 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.^[1] However, it also means that, when intracellular levels of Na⁺ rise beyond a critical point, the NCX begins importing Ca²⁺.^[1][8][9] 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.^[1]

Na⁺/Ca²⁺ exchanger in the cardiac action potential[edit]

The ability for the Na⁺/Ca²⁺ exchanger to reverse direction of flow manifests itself during the cardiac action potential. Due to the delicate role that Ca²⁺ plays in the contraction of heart muscles, the cellular concentration of Ca²⁺ is carefully controlled. During the resting potential, the Na⁺/Ca²⁺ exchanger takes advantage of the large extracellular Na+ concentration gradient to help pump Ca²⁺ out of the cell.^[10] In fact, the Na⁺/Ca²⁺ exchanger is in the Ca²⁺ efflux position most of the time. However, during the upstroke of the cardiac action potential there is a large influx of Na⁺ ions. This depolarizes the cell and shifts the membrane potential in the positive direction. What results is a large increase in intracellular [Na⁺]. This causes the reversal of the Na⁺/Ca²⁺ exchanger to pump Na⁺ ions out of the cell and Ca²⁺ ions into the cell.^[10] However, this reversal of the exchanger lasts only momentarily due to the internal rise in [Ca²⁺] as a result of the influx of Ca²⁺ through the L-type calcium channel, and the exchanger returns to its forward direction of flow, pumping Ca²⁺ out of the cell.^[10]

While the exchanger normally works in the Ca²⁺ efflux position (with the exception of early in the action potential), certain conditions can abnormally switch the exchanger to the reverse (Ca²⁺ influx, Na⁺ efflux) position. Listed below are several cellular and pharmaceutical conditions in which this happens.^[10]

• The internal [Na⁺] is higher than usual (like it is when digitalis glycoside medications block the Na⁺/K⁺ -ATPase pump.)
• The Sarcoplasmic Reticulum release of Ca²⁺ is inhibited.
• Other Ca²⁺ influx channels are inhibited.
• If the action potential duration is prolonged.

Structure[edit]

Based on secondary structure and hydrophobicity predictions, NCX was initially predicted to have 9 transmembrane helices.^[11] The family is believed to have arisen from a gene duplication event, due to apparent pseudo-symmetry within the primary sequence of the transmembrane domain.^[12] Inserted between the pseudo-symmetric halves is a cytoplasmic loop containing regulatory domains.^[13] These regulatory domains have C2 domain like structures and are responsible for calcium regulation.^[14][15] Recently, the structure of an archaeal NCX ortholog has been solved by X-ray crystallography.^[16] This clearly illustrates a dimeric transporter of 10 transmembrane helices, with a diamond shaped site for substrate binding. Based on the structure and structural symmetry, a model for alternating access with ion competition at the active site was proposed. The structures of three related proton-calcium exhangers (CAX) have been solved from yeast and bacteria. While structurally and functionally homologus, these structures illustrate novel oligomeric structures, substrate coupling, and regulation.^[17][18][19]

History[edit]

In 1968, H Reuter and N Seitz 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.^[2][20] In 1969, a group led by PF Baker that was experimenting using squid axons published a finding that proposed that there exists a means of Na⁺ exit from cells other than the sodium-potassium pump.^[2][21]

See also[edit]

• Active transport
• Cardiac action potential
• Potassium-dependent sodium-calcium exchanger

References[edit]

External links[edit]

• Sodium-calcium exchanger at the US National Library of Medicine Medical Subject Headings (MeSH)
• Diagram at cvphysiology.com
• Klabunde, RE. 2007. Cardiovascular Physiology Concepts: Calcium Exchange.