K+-AGGRAVATED MYOTONIA - DESTABILIZATION OF THE INACTIVATED STATE OF THE HUMAN MUSCLE NA+ CHANNEL BY THE V1589M MUTATION

1. Wild type (WT) and V1589M channels were expressed in human embryonic kidney (HEK293) eels for the study of the pathophysiology of the V1589M muscle Na+ channel mutation leading to K+-aggravated myotonia. 2. In comparison to WT, whole-cell recordings with V1589M channels showed an increased Na+ steady-state to peak current ratio (I-ss/I-peak) (3.15+/-0.70 vs. 0.87+/-0.10%, at -15 m V) and a significantly faster recovery from inactivation. The recovery time constants, tau(r1) and tau(r2) were decreased from 1.28+/-0.12 to 0.92+/-0.08 ms and from 4.74+/-0.94 to 2.66+/-0.51 ms for the WT and mutant channels, respectively. 3. Single-channel recordings with mutant channels showed higher probability of short isolated late openings (0.40+/-0.09 vs. 0.06+/-0.02, at -30 m V) and bursts of late openings (0.011+/-0.003 vs. 0.003+/-0.001, at -30 m V) compared to WT. 4. These results suggest that the mutation increases the probabilities for channel transitions from the inactivated to the closed and the opened states. 5. Increased extracellular concentrations of K+ had no effects on either V1589M or WT currents in HEK293 cells. The aggravation of myotonia seen in patients during increased serum K+ may arise from the associated membrane depolarization which favours the occurrence of late openings in the mutant channel.