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Cytoskeleton modulates coupling between availability and activation of cardiac sodium channel.

The aim of this study was to investigate modulation of voltage-dependent steady-state activation and availability from inactivation of the cardiac Na+ channel by the cytoskeleton. As an experimental approach, we used long-lasting monitoring [63 +/- 5 (SE) min] of the half-point potentials of the steady-state availability curve (V(1/2A)) and normalized conductance curve (V(1/2G)) in 116 rat ventricular cardiomyocytes by whole cell patch clamp at 22-24 degrees C. Both half-point potentials shifted in the negative direction with time as an exponentially saturating change, with the shift of V(1/2G) being smaller and faster. An F-actin disrupter, cytochalasin D (Cyto-D, 20 microM), accelerated the rate of the V(1/2A) shift but decreased the range of the V(1/2G) shift. An F-actin stabilizer, phalloidin (100 microM), temporarily (for 28.2 +/- 2.2 min, n = 15) prevented the V(1/2A) shift but did not influence the V(1/2G) shift. The best fit for the V(1/2G)-V(1/2A) relationship in untreated cells (1,021 data points measured in 51 cells) was a second-degree (2.06) power function. Cytoskeleton-directed agents modified the relationship. In Cyto-D-treated cells, the V(1/2G)-V(1/2A) relationship was shifted (by 2.5 mV) toward positive V(1/2G). On the contrary, a microtubule stabilizer, taxol (100 microM), shifted the relationship toward negative V(1/2G) (by 12.2 mV). We conclude that coupling between availability and activation is modulated by F-actin-based and microtubular cytoskeleton.