I_Ca(TTX) channels are distinct from those generating the classical cardiac Na⁺ current

The Na⁺ current component I_Ca(TTX) is functionally distinct from the main body of Na⁺ current, I_Na. It was proposed that I_Ca(TTX) channels are I_Na channels that were altered by bathing media containing Ca²⁺, but no, or very little, Na⁺. It is known that Na⁺-free conditions are not required to demonstrate I_Ca(TTX). We show here that Ca²⁺ is also not required. Whole-cell, tetrodotoxin-blockable currents from fresh adult rat ventricular cells in 65 mm Cs⁺ and no Ca²⁺ were compared to those in 3 mM Ca²⁺ and no Cs⁺ (i.e., I_Ca(TTX). I_Ca(TTX) parameters were shifted to more positive voltages than those for Cs⁺. The Cs⁺ conductance-voltage curve slope factor (mean, -4.68 mV; range, -3.63 to -5.72 mV, eight cells) is indistinguishable from that reported for I_Ca(TTX) (mean, -4.49 mV; range, -3.95 to -5.49 mV). Cs⁺ current and I_Ca(TTX) time courses were superimposable after accounting for the voltage shift. Inactivation time constants as functions of potential for the Cs⁺ current and I_Ca(TTX) also superimposed after voltage shifting, as did the inactivation curves. Neither of the proposed conditions for conversion of I_Na into I_Ca(TTX) channels is required to demonstrate I_Ca(TTX). Moreover, we find that cardiac Na⁺ (H1) channels expressed heterologously in HEK 293 cells are not converted to I_Ca(TTX) channels by Na⁺-free, Ca²⁺-containing bathing media. The gating properties of the Na⁺ current through (H1) and those of Ca²⁺ current through H1 are identical. All observations are consistent with two non-interconvertable Na⁺ channel populations: A larger that expresses little Ca²⁺ permeability and a smaller that is appreciably Ca²⁺ -permeable.