Sodium-calcium exchanger

The sodium–calcium exchanger is only one of the systems by which the cytoplasmic concentration of calcium ions in the cell is kept low. The 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] Such a primary transporter of calcium ions is present in the plasma membrane of most animal cells. 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] The Na⁺/Ca²⁺ exchanger complements the high affinity, low capacitance Ca²⁺-ATPase and together, they are involved in a variety of cellular functions including:

• 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.

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] This effect may prolong calcium transients following bursts of neuronal activity, thus influencing neuronal information processing.[10][11]

Based on secondary structure and hydrophobicity predictions, NCX was initially predicted to have 9 transmembrane helices.[13] 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.[14] Inserted between the pseudo-symmetric halves is a cytoplasmic loop containing regulatory domains.[15] These regulatory domains have C2 domain like structures and are responsible for calcium regulation.[16][17] Recently, the structure of an archaeal NCX ortholog has been solved by X-ray crystallography.[18] 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 exchangers (CAX) have been solved from yeast and bacteria. While structurally and functionally homologus, these structures illustrate novel oligomeric structures, substrate coupling, and regulation.[19][20][21]

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][22] 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][23] Digitalis, more commonly known as foxglove, is known to have a large effect on the Na/K ATPase, ultimately causing a more forceful contraction of the heart. The plant contains compounds that inhibit the sodium potassium pump which lowers the sodium electrochemical gradient. This makes the pumping of calcium out of the cell less efficient, which leads to a more forceful contraction of the heart. For individuals with weak hearts, it is sometimes provided to pump the heart with heavier contractile force. However, it can also cause hypertension because it increases the contractile force of the heart.

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

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