To address the pathogenesis of HypoPP caused by CACNA1S
mutations, Wu and colleagues in the laboratory of Stephen Cannon report in this issue of the JCI
the investigation of a novel knock-in mouse model of the disease (20
). Mice were generated that express the most common human HypoPP mutation (CaV
1.1 R528H), a histidine substitution for the outermost arginine residue of the D2/S4 segment in CaV
1.1. Although animals did not exhibit spontaneous attacks of weakness, muscle strength was reduced more severely in male mice, consistent with the reduced penetrance in females observed for human HypoPP (6
). Muscles from knock-in mice exhibited features previously observed in human HypoPP fibers, including reduced contractile force and paradoxical membrane depolarization evoked by low extracellular potassium or by glucose and insulin challenge. Muscle fibers from homozygous knock-in R528H mice exhibited a –15-mV depolarization of the resting membrane potential similar to human HypoPP fibers. In addition, these mice exhibited a chronic vacuolar myopathy similar to that observed in patients with this disorder.
A critical observation made by these investigators was the presence of an anomalous inward current in mutant mouse muscle fibers consistent with gating pore current rather than ionic current conducted through a known ion channel (20
). These findings offered a mechanistic link between calcium channel mutation and attacks of muscle weakness. Anomalous gating pore current creates a precarious balance between the inward and outward currents that maintain the membrane potential. Factors such as hypokalemia that transiently depress potassium currents, which are required to maintain a normal resting membrane potential, can render the muscle severely depolarized and, consequently, inexcitable owing to inactivation of sodium channels.
Now that a common mechanism of evoking gating pore current has been established in HypoPP, several new and intriguing questions emerge. Can aberrant gating pore current be selectively blocked, and would this prevent attacks of paralysis? Do carbonic anhydrase inhibitors such as acetazolamide and dichlorphenamide, which are effective treatments for HypoPP regardless of genotype, affect gating pore current directly or indirectly? Are there triggering factors that act specifically by potentiating gating pore current? Finally, what is the basis for vacuolar myopathy, and why is there a sex-biased penetrance of mutations? These and other important questions can now be addressed using the mouse model developed by Wu and colleagues.
Although HypoPP was the first channelopathy for which aberrant gating pore current was implicated in disease pathogenesis, many other S4 mutations in voltage-gated sodium, calcium, and potassium channels have been found in other inherited disorders of membrane excitability, including epilepsy and cardiac arrhythmia syndromes (21
). Are some of these conditions also “gating pore-opathies”? A recent study demonstrating that an S4 segment mutation in the cardiac sodium channel (NaV
1.5 R219H) associated with dilated cardiomyopathy evokes an aberrant proton current (22
) suggests that this may be a more widespread phenomenon.