Bridging the Gap between Anomalous Sodium Channel Molecules and Aberrant Physiology

Ours is a scientific era captivated by molecular reductionism. We often succumb to a belief that the key to understanding complex organisms resides in discovering the molecules and molecular properties that undergird macroscopic phenomena. Once the relevant molecular secrets are unlocked, the implications of their properties for macroscopic behavior is believed to be obvious and direct, at least in-the-large. The track record for this philosophical viewpoint can be quite convincing. Mutations in cone visual pigments explain differences in color perception (Merbs and Nathans, 1992). Long-term potentiation at synapses explains spatial learning (Silva et al., 1992a, 1992b). A chloride channel defect gives rise to cystic fibrosis (Rommens et al., 1989). This issue's paper by Cannon and Corey concerns the inherited disease of hyperkalemic periodic paralysis (HPP (Gamstorp, 1956)), one of the most beautiful examples of pathophysiological disorders explainable by the molecular reductionist approach. Patients with this affliction suffer attacks of muscular rigidity or flaccidity following modest elevations of serum [K+]. The molecular culprit appears to be a mutant voltage-gated sodium channel in skeletal muscle, which fails to inactivate with maintained depolarization. Yet, there has been a worrisome gap between the marked sequelae of the disease and the admittedly small defect found in sodium channel function. Could there be more to the story? Cannon and Corey do not add here to the molecular details of the picture; rather, their contribution is to elaborate mathematically the consequences of a very slight defect in sodium channel inactivation upon skeletal muscle excitability. Their analysis shows that very modest perturbations in sodium channel ing disturbances in skeletal muscle function. Beyond clarifying the molecular pathogenesis of HPP, Cannon and Corey's paper serves as an elegant reminder of the limitations of molecular reductionism, and the crucial need for other scientific approaches. To appreciate the full impact of their work, it is worth summarizing the quickening pace of research on HPP. Physiological studies of muscle derived from HPP patients began to implicate faulty sodium channels as the root cause of the disease. In the mid 1980s, Lehmann-Horn and others provided preliminary evidence that an increase in extracellular [K] produced excess depolarization in muscle fibers biopsied from HPP patients. Coarse voltage clamp measurements showed that modest depolarization activated a small, noninactivating inward current that was blockable by tetrodotoxin. They surmized that sodium channels defective in inactivation could be the cause of HPP. Cannon et al. (1991) provided the single-channel evidence that something was indeed awry with sodium channels of myotubes cultured from HPP patients. Not only did a significant fraction of sodium channels fail to inactivate, but the unusual lack of inactivation was observed only when extracellular [K] was raised. This provided a most satisfying molecular explanation for the K+ dependence of HPP attacks. Work from several laboratories used genetic approaches to show tight linkage ofHPP inheritance to the adult skeletal muscle sodium channel gene on chromosome 17. Two specific mutations were later found in the coding region of the skeletal muscle sodium channel, and both were very unlikely to represent benign polymorphisms. Finally, the sodium channel mutations identified in HPP patients were introduced into wild-type sodium channels, expressed in mammalian cells. These channels failed to inactivate to the extent observed in wild-type channels (Cannon and Strittmatter, 1993), thereby building an apparently air-tight case for the causative role of mutant sodium channels in HPP. Nevertheless, there remained some ure of sodium channels to inactivate occurred in only a few percent of the sodium channels (Cannon et al., 1991). It seemed a leap of faith to expect that this miniscule alteration in sodium channel gating could produce the broad panora-