O. Moran et al., Fast- and slow-gating modes of the sodium channel are altered by a paramyotonia congenita-linked mutation, J BIOENER B, 30(6), 1998, pp. 579-588
We have studied the expression in frog oocytes of the alpha subunit of the
rat skeletal muscle sodium channel mutation T1306M, homologous to the mutat
ion T1313M of the human isoform that causes the muscular hereditary disease
paramyotonia congenita. Wild-type (WT) channels show a bimodal behavior, w
ith two gating modes characterized by inactivation time constants that diff
er at least by one order of magnitude and with voltage dependencies shifted
by +27 mV in the slow mode (M2) relative to the fast (M1) mode. In the myo
pathy-linked mutant the propensity of the channel for the mode M2 is increa
sed fourfold and the kinetics and voltage dependence of inactivation in bot
h modes are altered. In mode M1, the onset of inactivation is faster and th
e recovery from inactivation is slower whereas both processes are stowed in
mode M2. The half-inactivation potential of both modes is shifted by the m
utation to positive potentials. Coexpression of beta subunit causes a three
fold reduction of the M2 propensity of both WT and T1306M channels, with sm
all changes in the voltage dependency and kinetic properties of inactivatio
n. All the changes are consistent with the hyperexcitability of the muscle
fibers observed in patients affected by potassium-aggrevated myotonia (PAM)
.