Steady-state and dynamic properties of cardiac sodium-calcium exchange. Secondary modulation by cytoplasmic calcium and ATP.

Abstract

Dynamic responses of cardiac sodium-calcium exchange current to changes of cytoplasmic calcium and MgATP were monitored and analyzed in giant membrane patches excised from guinea pig myocytes. Secondary dependencies of exchange current on cytoplasmic calcium are accounted for in terms of two mechanisms: (a) The sodium-dependent inactivation process, termed Ii modulation, is itself strongly modulated by cytoplasmic calcium. Recovery from the I1 inactivated state is accelerated by increasing cytoplasmic calcium, and the calculated rate of entrance into I1 inactivation is slowed. (b) A second modulation process, termed I.o modulation, is not sodium dependent. As with Il modulation, the entrance into I2 inactivation takes place over seconds in the absence of cytoplasmic calcium. The recovery from I2 inactivation is a calcium-dependent transition and is rapid (< 200 ms) in the presence of micromolar free calcium. Ii and I2 modulation can be treated as linear, independent processes to account for most exchange modulation patterns observed: (a) When cytoplasmic calcium is increased or decreased in the presence of high cytoplasmic sodium, outward exchange current turns on or off, respectively, on a time scale of multiple seconds. (b) When sodium is applied in the absence of cytoplasmic calcium, no outward current is activated. However, the flail outward current is activated within solution switch time when cytoplasmic calcium is applied together with sodium. (c) The calcium dependence of peak outward current attained upon application of cytoplasmic sodium is shifted by ~ 1 log unit to lower concentrations from the calcium dependence of steady-state exchange current. (d) The time course of outward current decay upon decreasing cytoplasmic calcium becomes more rapid as calcium is reduced into the submicromolar range. (e) Under nearly all conditions, the time courses of current decay during application of cytoplasmic sodium and/or removal of cytoplasmic calcium are well fit by single exponentials. Both of the modulation processes are evidently affected by MgATP.Address reprint requests to Donald W. Hilgemann,

Role of Na+/Ca2+exchanger in Ca2+homeostasis in rat suprachiasmatic nucleus neurons

“…Two factors may be responsible for the inability of 0 Na ϩ to induce Ca 2ϩ uptake via reverse NCX in control conditions. First, internal Ca 2ϩ is required for allosteric activation of NCX (DiPolo 1979;Hilgemann et al 1992a), and as such the lowering of [Ca 2ϩ ] i by 0 Na ϩ may prevent the activation of reverse NCX. Second, the lowering of [Na ϩ ] i during the application of Na ϩ -free solution may also inhibit the reverse mode of NCX.…”

Inhibition by KB-R7943 of the Reverse Mode of the Na+/Ca2+ Exchanger Reduces Ca2+ Overload in Ischemic-Reperfused Rat Hearts.

“…Inhibition of the NCX may be explained by a decrease in intracellular pH, 29,30 extracellular pH 31 and/or ATP. 32 We have demonstrated intracellular acidosis in intact hearts during global ischemia using a fluorescent intracellular pH indicator. 33 Taking these findings into consideration, how did KBR, 7 and this effect might inhibit functional activity of the reverse mode of the NCX.…”

Na+-Ca2+ Exchanger: Physiology and Pharmacology.

“…The Na+-dependent inactiva tion is reversible upon removal of Na+ and is specific for the Na+-bound configuration. Furthermore, the inactivation is exacerbated at acidic cytosolic pH (76) and can be attenuated by increasing intracellular Ca2+ and by ATP (77).…”