The action of Na+ as a cofactor in the inhibition by cytoplasmic protons of the cardiac Na(+)-Ca2+ exchanger in the guinea-pig.
1. Na(+)-Ca2+ exchange current was activated in giant excised patches of guinea-pig cardiac sarcolemma by raising the intracellular sodium concentration ([Na+]i). When the pHi was simultaneously acidified to 6.4, the current was transient, dropping by 80% in 30 s. 2. Pre-exposure to a pHi of 6.4 for 15 s reduced the peak Na(+)-Ca2+ exchange current without altering the decay rate or steady-state current. Recovery from proton inhibition was seen when [Na+]i was removed for 9 s. 3. A mathematical model of Na(+)-Ca2+ exchange function reproduced the experimental results. In addition, two model-dependent predictions were seen experimentally. (i) [Na+]i-dependent 'inactivation' of Na(+)-Ca2+ exchange may arise from pHi effects. We observed experimentally that pre-exposure to acidic pHi can remove the transient current component attributed to [Na+]i-dependent 'inactivation'. (ii) self-exchange should be inhibited by acidification. This has been observed by other investigators. 4. We have hypothesized that there are two components to inhibition of the Na(+)-Ca2+ exchanger by intracellular protons, and that one is enhanced by increased [Na+]i (Doering & Lederer, 1993b). This hypothesis is supported by the data presented here and by a model of Na(+)-Ca2+ exchange behaviour in which binding of intracellular sodium to the exchanger enhances the affinity of the exchanger for inhibitory intracellular protons.
Department of Physiology, University of Maryland School of Medicine, Baltimore 21201.
A E
AE
Doering
W J
WJ
Lederer
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism*; D006168:Guinea Pigs; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008954:Models, Biological; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D012508:Sarcolemma / Q000187:drug effects / Q000378:metabolism; D012964:Sodium / Q000378:metabolism / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger
D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; D012964:Sodium; D002118:Calcium