In dialyzed squid axons oxidative stress inhibits the Na+/Ca2+ exchanger by impairing the Ca2+i-regulatory site

DIPOLO, R. AND BEAUGÉ, L

American Journal of Physiology Cell Physiology

American Journal of Physiology

Lugar: Washington; Año: 2011 vol. 301 p. 687 - 694

1522-1563

The Na+/Ca2+ exchanger, a major mechanism by which cells extrude calcium, is involved in several physiological and physiopathological interactions. In this work we have used the dialyzed squid giant axon to study the effects of two oxidants, NSI-1 buffered peroxynitrite and hydrogen peroxide (H2O2), on the Na+/Ca2+ exchanger in the absence and presence of MgATP up-regulation. The results show that oxidative stress induced by peroxynitrite and hydrogen peroxide inhibits the Na+/Ca2+ exchanger by impairing the Ca2+i-regulatory sites, leaving unharmed the intracellular Na+ and Ca2+ transporting sites. This effect is efficiently counteracted by MgATP, a ligand that also protects H+i and (H+i + Na+i) inhibition of Ca2+i-regulatory sites. In addition, 1 mM intracellular EGTA reduces oxidant inhibition. However, once the effects of oxidants are installed they cannot be reversed by either MgATP or EGTA. These results have significant implications regarding the role of the Na+/Ca2+ exchanger in pathological conditions such as cell ischemia and anoxia that lead to a marked reduction in ATP concentration, an increase in oxidant production, and a rise in intracellular Ca2+ concentration that seems to be the main factor responsible for cell damage.