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Regulation and deregulation of cardiac Na+–Ca2+ exchange in giant excised sarcolemmal membrane patches

Abstract

A PLASMALEMMAL Na+–Ca2+ exchange mechanism1,2 is an important electrogenic determinant of contractility in cardiac cells3–5. As in other cell types6–8, calcium influx by Na+–Ca2+" exchange is secondarily activated by cytoplasmic calcium4 and probably ATP9, but these modulatory mechanisms are either absent or altered in isolated cardiac sarcolemmal vesicles5,12. Involvement of a calcium-dependent protein kinase in exchange regulation has been suggested7,10 but not verified5,11. Here I describe measurements of outward Na+–Ca2+ exchange current, corresponding to calcium influx, in giant excised sarcolemmal Patches11 from guinea pig myocytes. The exchange current is stimulated by both calcium and Mg–ATP from the cytoplasmic face, evidently through separate mechanisms. Activation by cytoplasmic calcium takes place within seconds, is reversible, and does not require ATP. Stimulation by Mg–ATP reverses only slowly over > 10 min, or not at all. Unexpectedly, a substantial decrease in exchange current occurs during activation by cytoplasmic sodium, which seems to reflect an inactivation process rather than ion concentration changes or a 'first pass' exchange cycle. This apparent inactivation, and the modulations by cytoplasmic calcium and Mg–ATP, are all abolished by brief treatment of the cytoplasmic surface with chymotrypsin, leaving the exchanger in a maintained state of high activity. Therefore, limited proteolysis deregulates Na+–Ca2+ exchange and could contribute to the loss of secondary regulation of the exchange in isolated sarcolemmal vesicles.

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Hilgemann, D. Regulation and deregulation of cardiac Na+–Ca2+ exchange in giant excised sarcolemmal membrane patches. Nature 344, 242–245 (1990). https://doi.org/10.1038/344242a0

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