Exact(11)
Experimental data and the results of numerical modeling accumulated over the past decade show the emerging importance of this late current component for the function of both normal and failing myocardium.
Thus altered window current by itself does not account for the F1473C-induced increase in late current.
The sustained current observed in patch clamp experiments was modeled as an increased probability of entering a bursting mode of channel openings, based on the observed broad voltage-dependence of mutation-enhanced late current.
Figure 2D, which presents summary data, shows that the F1473C mutation causes a 6-fold increase in non-inactivating late current (INaL) measured at 200ms during pulses to −10 mV (WT: INaL = 0.1+/−0.01%, n = 11 and F1473C: INaL = 0.63+/−0.05%, n = 31; p<1.5e-05), which is plotted as the percentage of peak current.
First, compared with WT channels there is a very large increase in non-inactivating current for F1743C channels over the duration of the voltage pulse to +20 mV, confirming that the mutation-induced late current is evident beyond the range of inactivation/activation curve overlap (window current).
NaV late current and the time constant of inactivation were not different from shRNA.
Similar(49)
Because these experiments focused on peak and not late currents, we used extracellular solutions containing reduced [Na+] (Methods S1 (supplemental methods)) to ensure adequate voltage control.
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