Sodium Channel Gating Modes During Redox Reaction

Abstract

Background/Aims: Many studies have confirmed that persistent sodium current (I_NaP) is altered during a redox reaction, but little attention has been paid to transient sodium current (I_NaT) and its correlation with I_NaP during the redox reaction. The aim of the study was to investigate the effect of the redox states on the correlation between I_NaT and I_NaP in cardiomyocytes. Methods: I_NaT and I_NaP were recorded using whole-cell and cell-attached patch-clamp techniques in guinea pig ventricular myocytes. Results: In whole-cell recordings, dithiothreitol (DTT, 1 mM) simultaneously increased I_NaT and decreased I_NaP. Hydrogen peroxide (H₂O₂, 0.3 mM) increased I_NaP and decreased I_NaT in a time-dependent manner, which were reversed by DTT (1 mM). In cell-attached recordings, the increasing of I_NaP and decreasing of I_NaT induced by H₂O₂ (0.3 mM) were similarly recovered by DTT (1 mM). H₂O₂ (0.3 mM) prolonged the action potential (AP) duration of ventricular papillary cells whereas decreased the AP amplitude and maximum rate of depolarization (V_max) in a time-dependent manner, which were reversed by DTT (1 mM). Conclusion: These results indicate that the redox states could modulate the sodium channel gating modes in guinea pig ventricular myocytes.

Redox Control of Cardiac Excitability

“…They distribute in the four S5-S6 linkers, intracellular linkers between domains I and II, II and III, and other regions of the channel (18). Thus H 2 O 2 , GSH/GSSG, DTT, and perhaps hypoxia could change the gating mode of the sodium channel by directly acting on one or more cysteine residues in the sodium channel (166). In this regard, NO and perhaps the RNS are shown to decrease the I NaP and I NaT possibly by Snitrosylation of the cysteine residues on the a-subunit of the Na + channel (3,253).…”

“…In particular, signaling pathways that regulate cardiac Na + channel function include activation of PKA, PKC, and CaMKII (Fig. 16), both of which as activated by ROS (166). The PKA phosphorylates two serine residues (S525 and S528 in the human cardiac isoform) within the DI-DII linker that augments the I Na (82), whereas PKC phosphorylates S1505 in the DIII-DIV inactivation gate (217) that causes a reduction in the current amplitude at hyperpolarized ( -94 mV) holding potential.…”

Hydrogen sulfide is a partially redox-independent activator of the human jejunum Na+ channel, Nav1.5

“…In general, reducing agents either can shift the voltage dependence of steady-state activation and inactivation to more positive potentials (5) or increase peak current (5,18). In contrast, oxidizing reagents shift steady-state inactivation to more negative potentials or reversibly inhibit peak current (5,18,21,37) ( Table 1). The mechanisms of these effects are not clear.…”

Tolterodine reduces veratridine-augmented late INa, reverse-INCX and early afterdepolarizations in isolated rabbit ventricular myocytes

“…Previous studies indicated that late sodium current (I Na.L ), which is tetrodotoxin (TTX)-sensitive [1] , was increased under various pathological conditions, such as long QT syndrome III, myocardial hypertrophy, heart failure, ischemia, anoxia, and oxidative stress [2][3][4][5][6][7][8][9][10] . Although it has a much smaller amplitude than the transient sodium current (I Na.T ) under normal conditions, I Na.L plays an important role in determining the plateau of action potential (AP) and action potential duration (APD) under the above pathological conditions [11,12] .…”