Cytoskeleton modulates gating of voltage-dependent sodium channel in heart.
To investigate the role of the cytoskeleton in cardiac Na+ channel gating, the action of cytochalasin D (Cyto-D), an agent that interferes with actin polymerization, was studied by whole cell voltage clamp and cell-attached and inside-out patches from rat and rabbit ventricular cardiac myocytes. Cyto-D (20-40 microM) reduced whole cell peak Na+ current by 20% within 12 min and slowed current decay without affecting steady-state voltage-dependent availability or recovery from inactivation. Brief treatments (< 10-15 min) of cell-attached patches by Cyto-D (20 microM) in the bath induced short bursts of Na+ channel openings and prolonged decays of ensemble-averaged currents. Bursting of the Na+ channel was more pronounced when the cell suspension was pretreated with Cyto-D (20 microM) for 1 h before seal formation. Application of Cyto-D on the cytoplasmic side of inside-out patches resulted in more dramatic gating changes. Peak open probability was reduced by > 50% within 20 min, and long bursts of openings occurred. Washout of Cyto-D did not restore ensemble-averaged current amplitude, but burst duration decreased toward control values. Cyto-D also induced an additional slower component to open and closed times. These results suggest that Cyto-D, through effects on cytoskeleton, induced cardiac Na+ channels to enter a mode characterized by a lower peak open probability but a greater persistent activity as if the inactivation rate was slowed. The cytoskeleton, in addition to localizing integral membrane proteins, apparently also plays a role in regulating specific detailed functions of integral membrane proteins such as the gating of Na+ channels.
Undrovinas
A I
AI
Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, Michigan 48202, USA.
Shander
G S
GS
Makielski
J C
JC
D000818:Animals; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000502:physiology*; D004594:Electrophysiology; D015640:Ion Channel Gating / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D015222:Sodium Channels / Q000187:drug effects / Q000502:physiology*
D015222:Sodium Channels; D015638:Cytochalasin D