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.
Maltsev
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Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan 48202-2689, USA.
Undrovinas
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D000818:Animals; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000502:physiology*; D004553:Electric Conductivity; D006706:Homeostasis; D066298:In Vitro Techniques; D008955:Models, Cardiovascular; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010590:Phalloidine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000502:physiology*
D015222:Sodium Channels; D010590:Phalloidine; D015638:Cytochalasin D; D017239:Paclitaxel