Sodium channelopathies of skeletal muscle result from gain or loss of function

Abstract

Five hereditary sodium channelopathies of skeletal muscle have been identified. Prominent symptoms are either myotonia or weakness caused by an increase or decrease of muscle fiber excitability. The voltage-gated sodium channel NaV1.4, initiator of the muscle action potential, is mutated in all five disorders. Pathogenetically, both loss and gain of function mutations have been described, the latter being the more frequent mechanism and involving not just the ion-conducting pore, but aberrant pores as well. The type of channel malfunction is decisive for therapy which consists either of exerting a direct effect on the sodium channel, i.e., by blocking the pore, or of restoring skeletal muscle membrane potential to reduce the fraction of inactivated channels.

Fig. 1

α-Subunit of the voltage-gated sodium channel of skeletal muscle, Na_V1.4. The alpha-subunit is composed of four highly homologous domains (DI–DIV) each consisting of six transmembrane segments (S1–S6). When inserted in membrane, the four domains of the protein fold to generate a central pore whereby the S5–S6 loops form the ion-selective pore. The S4 segments contain positively charged residues conferring voltage dependence to the protein. Domains are connected by intracellular loops; one of them, the DIII−DIV linker, contains the inactivation particle of the channel. The sketch gives an overview of locations of known Na_V1.4 mutations

Fig. 2

Currents through WT and mutant sodium channels. a Whole-cell sodium current traces of WT and PAM mutant (G1306V) sodium channels. b Single-channel recordings for WT and mutant sodium channels. Sodium currents were elicited by step depolarizations from a holding potential of −120 mV in 10 mV steps to +30 mV. Re-openings were more frequent for mutant channels, thereby leading to a small persistent current. Modified after Mitrovic et al. [34]

Fig. 3

Leak currents. a A replacement of the outermost arginine (red) by a smaller amino acid (blue), e.g., glycine, opens a conductive pathway at hyperpolarized potentials, resulting in an inward cation current (blue). At depolarized potentials at which the S4 segment moves outward, the conductive pathway is closed and the cation current ceases. b Schematic of cation currents through sodium channels carrying charge-neutralizing substitutions in S4 voltage sensors. Note the large inward current in the hyperpolarized potential range corresponding to the resting state of the leaky S4 voltage sensor

Fig. 4

Bistable membrane potentials and pathogenesis of hypokalemic periodic paralysis. a Bifurcation diagram of a mathematical model of skeletal muscle with the extracellular K⁺ concentration as the control parameter. Beginning at high K⁺ concentrations, a reduction reveals an instability of the resting potential at the limit point, LP1 (closed circles), from which a sudden transition to about −60 mV occurs. Increasing the K⁺ concentration from low values takes the muscle fiber to another limit point, LP2 (open circles), where the system jumps back into a state with normal membrane potentials. Control (red line), additional small (5 µS/cm²) depolarizing current and insulin-induced reduction of Kir conductance as in HypoPP (blue line), regions of instability (dashed line). b Fraction of rat diaphragm muscle fibers with normal membrane potentials after the reduction of [K⁺]_o to different values, without (red) and with (blue) amphotericin B, a Na⁺ and K⁺ ionophore. Curves represent fits of a log-normal cumulative distribution function (modified from [23]). c Probability density functions computed with fit parameters from (b). These functions give the probability of a transition from the normal to the depolarized state for responding fibers at different [K⁺]_o. LP1 may be defined as the mode or the median of the curves. Amphotericin B causes an increment of mode, median, and SD by 1 mM, 1.5 mM, and 1.2 mM, respectively. Therefore, in the presence of a small depolarizing leak current, LP1 is shifted to the right and a paradoxical depolarization is more likely to occur even at normal [K⁺]_o