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 I1 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 I2 modulation, is not sodium dependent. As with I1 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. I1 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 full 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 approximately 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. Similar
to the effects of cytoplasmic calcium, MgATP slows the entrance into
I1 inactivation and accelerates the recovery from inactivation. MgATP
additionally slows the decay of outward exchange current upon removal
of cytoplasmic calcium by 2-10-fold, indicative of an effect on I2
inactivation. Finally, the effects of cytoplasmic calcium on sodium-calcium
exchange current are reconstructed in simulations of the I1 and I2
modulation processes as independent reactions.
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