Two cases of adynamia episodica hereditaria: In vitro investigation of muscle cell membrane and contraction parameters

Abstract

Membrane potentials, current-voltage relationships, and contractile parameters were studied in intact muscle cell bundles obtained from two patients with adynamia episodica hereditaria. In a normal extracellular medium, the cell membranes had resting potentials of about -80 mV and their current-voltage relationships were not significantly different from control curves. In contrast to normal muscles the afflicted cells were paralyzed in a medium having 6-10 mmol/liter potassium. The mechanisms of paralysis in the two specimens were different from each other. Many fibers from one patient were spontaneously active even in normal solution. In high potassium solution spontaneous activity was increased and the cells gradually depolarized to values at which excitatory sodium current is normally inactivated. This depolarization was connected with an increased sodium conductance and was reversed by the application of tetrodotoxin (TTX). The fibers from the other patient were not spontaneously active. In high potassium solution they were paralyzed at membrane potential values at which normal fibers would still contract. The reason for this paralysis was a reduced excitability.

Ranolazine block of human Nav1.4 sodium channels and paramyotonia congenita mutants

“…28 An important characteristic of paramyotonia congenita mutant channels is increased persistent I Na , which produces muscle fiber inexcitability, followed by paralysis. 10,12,14,22 In the present study, the presence of increased persistent I Na in cells expressing the paramyotonia congenita mutation, R1448C was observed using slow depolarizing ramps. At 3 μM, which is within the potential resulted in excessive and sustained action potential firing (myotonic activity).…”

“…Mutation of this positively charged arginine results in the general set of biophysical defects associated with paramyotonia congenita mutants, including slowed whole-cell current inactivation, reduced voltage-dependence of inactivation, enhanced rate of the recovery from inactivation and increased tetrodotoxin (TTX)-sensitive persistent (late) I Na . [7][8][9][10][11][12] These features lead to enhanced Na + entry into the cell causing depolarization of the resting membrane potential and sustained action potential firing which results in hyperexcitability (myotonia) or inexcitability (paralysis). 10,13,14 Current therapies for patients with…”

Cromakalim (BRL 34915) restores in vitro the membrane potential of depolarized human skeletal muscle fibres

“…It has been previously described that h.p.p, muscle fibres respond with an activation of a non-inactivating Na + conductance when [K+]e is slightly elevated (Lehmann-Horn et al 1983, 1987a. As a consequence, the membrane depolarizes more than predicted by the Nernst equation for a given increase in [K+]c. Furthermore, Em remains depolarized even when [K+]c is lowered to the normal value.…”

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

“…A 2-compartment model of the muscle surface membrane and t tubule system suggested that the exaggerated excitability in HyperKPP depends on both the proportion of noninactivating Na + channels and the degree of activity-driven K + accumulation within t tubules (21,23,24). Consistent with this, electrophysiological analyses of muscle bundles from individuals with HyperKPP show that paralysis is caused by aberrant depolarization of the muscle membrane (3,15,16,25), but a link to the clinical triggers is incompletely understood.…”

“…The detection of an aberrantly increased inward Na + current in muscle from HyperKPP patients (15,16) preceded the linkage of HyperKPP to a locus near the SCN4A gene encoding Na V 1.4 (17). Subsequent studies identified more than 30 missense mutations in SCN4A among individuals with overlapping phenotypes of Hyper-KPP and related disorders (1,2,18).…”