Small G-protein RhoA is a potential inhibitor of cardiac fast sodium current

Small G-proteins of Rho family modulate the activity of several classes of ion channels, including K⁺ channels Kv1.2, Kir2.1, and ERG; Ca²⁺ channels; and epithelial Na⁺ channels. The present study was aimed to check the RhoA potential regulatory effects on Na⁺ current (I_Na) transferred by Na⁺ channel cardiac isoform Na_V1.5 in heterologous expression system and in native rat cardiomyocytes. Whole-cell patch-clamp experiments showed that coexpression of Na_V1.5 with the wild-type RhoA in CHO-K1 cell line caused 2.7-fold decrease of I_Na density with minimal influence on steady-state activation and inactivation. This effect was reproduced by the coexpression with a constitutively active RhoA, but not with a dominant negative RhoA. In isolated ventricular rat cardiomyocytes, a 5-h incubation with the RhoA activator narciclasine (5 × 10^-6 M) reduced the maximal I_Na density by 38.8%. The RhoA-selective inhibitor rhosin (10^-5 M) increased the maximal I_Na density by 25.3%. Experiments with sharp microelectrode recordings in isolated right ventricular wall preparations showed that 5 × 10^-6 M narciclasine induced a significant reduction of action potential upstroke velocity after 2 h of incubation. Thus, RhoA might be considered as a potential negative regulator of sodium channels cardiac isoform Na_V1.5.