The sodium-calcium exchanger (often denoted Na+/Ca2+ exchanger, exchange protein, or NCX) 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+). A single calcium ion is exported 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]
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:
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.
Dado que el transporte es electrogénico (altera el potencial de membrana), la despolarización de la membrana puede invertir la dirección del intercambiador si la célula está lo suficientemente despolarizada, como puede ocurrir en la excitotoxicidad . [1] Además, al igual que con otras proteínas de transporte, la cantidad y dirección del transporte depende de los gradientes de sustrato transmembrana. [1] Este hecho puede ser protector porque los aumentos en la concentración de Ca 2+ intracelular que ocurren en la excitotoxicidad pueden activar el intercambiador en dirección directa incluso en presencia de una concentración extracelular de Na + reducida . [1] Sin embargo, también significa que, cuando los niveles intracelulares de Na + aumentan más allá de un punto crítico, el NCX comienza a importar Ca 2+ . [1] [8] [9] El NCX puede operar en dirección directa e inversa simultáneamente en diferentes áreas de la célula, dependiendo de los efectos combinados de los gradientes de Na + y Ca 2+ . [1] Este efecto puede prolongar los transitorios de calcio después de estallidos de actividad neuronal, influyendo así en el procesamiento de la información neuronal. [10] [11]
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.[12] 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.[12] 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.[12]
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.[12]
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.
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