SLOW INACTIVATION IN HUMAN CARDIAC SODIUM-CHANNELS

The available pool of sodium channels, and thus cell excitability, is regulated by both fast and slow inactivation. In cardiac tissue, the r equirement for sustained firing of long-duration action potentials sug gests that slow inactivation in cardiac sodium channels may differ fro m slow inactivation in skeletal muscle sodium channels. To test this h ypothesis, we used the macropatch technique to characterize slow inact ivation in human cardiac sodium channels heterologously expressed in X enopus oocytes. Slow inactivation was isolated from fast inactivation kinetically (by selectively recovering channels from fast inactivation before measurement of slow inactivation) and structurally (by modific ation of fast inactivation by mutation of IFM1488QQQ). Time constants of slow inactivation in cardiac sodium channels were larger than previ ously reported for skeletal muscle sodium channels. In addition, stead y-state slow inactivation was only 40% complete in cardiac sodium chan nels, compared to 80% in skeletal muscle channels. These results sugge st that cardiac sodium channel slow inactivation is adapted for the su stained depolarizations found in normally functioning cardiac tissue. Complete slow inactivation in the fast inactivation modified IFM1488QQ Q cardiac channel mutant suggests that this impairment of slow inactiv ation may result from an interaction between fast and slow inactivatio n.