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

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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 inactivacion 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.

Original languageEnglish (US)
Pages (from-to)242-245
Number of pages4
JournalNature
Volume344
Issue number6263
StatePublished - Mar 15 1990

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Calcium
Adenosine Triphosphate
Membranes
Chymotrypsin
Muscle Cells
Proteolysis
Guinea Pigs
Sodium
Ions

ASJC Scopus subject areas

  • General

Cite this

Regulation and deregulation of cardiac Na+-Ca2+ exchange in giant excised sarcolemmal membrane patches. / Hilgemann, Donald W.

In: Nature, Vol. 344, No. 6263, 15.03.1990, p. 242-245.

Research output: Contribution to journalArticle

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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 inactivacion 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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AB - 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 inactivacion 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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