Overexcited or inactive: Ion channels in muscle disease

Overview All animals are equipped with the capacity for rapid motor response that excitable cells-nerve and muscle-mediate. Voltage-sensitive ion channels on the surface membranes allow the cells to generate brief and reversible alterations of the voltage (action potentials) along the surface of these cellular cables. Ion channels, notably those conducting Na +, Ca 2+, and W, are large proteins with membrane spanning pores that are regulated by both voltage sensors and gates in the same polypeptide. The critical role of ion channels in all excitable cells, and the complex interplay of activation and inactivation of the different ion currents underlying the action potential, has led many to suggest that inherited defects of voltage-sensitive channels could be incompatible with life. This view dramatically changed four years ago when the gene coding for the major ~ subunit of the human muscle sodium channel was isolated, localized to chromosome 17q, and found to show genetic linkage to hyperka-lemic periodic paralysis (hyperPP) (Fontaine et al., 1990). Patients with this hereditary disorder show episodic loss of excitability of skeletal muscle. Soon after, two additional muscle disorders, paramyotonia congenita (PC) and potassium aggravated myotonia (PAM), were linked to this same locus (Koch et al., 1991 ; Ptd~ek et al., 1991a; Ebers et al., 1991). The most common inherited disorder of horses was then found to be linked to the equine homolog of the same gene (Rudolph et al., 1992). Over the last two years, two additional human hereditary muscle diseases showing membrane excitation abnormalities , myotonia congenita (MC) and hypokalemic periodic paralysis (hypoPP), were linked to genes encoding the chloride and calcium ion channels (Koch et al., 1992; Fon-taine et al., 1994). As the amino acid changes underlying these disorders have been identified and characterized, this disease-based research has complemented ongoing in vitro mutagenesis and electrophysiological studies in the search for structure-function relationships in the channel molecules. Thus far, accumulated knowledge has resulted in a greater understanding of most facets of these disorders, from basic molecular pathophysiology to better patient diagnosis and management. The Muscle Sodium Channel Diseases The three hereditary muscle diseases in this group (hyperPP, PC, and PAM; see Rfidel et al., 1993, for review) are all inherited as dominant traits. Interestingly, the patho-physiology includes both hyper-and hypoexcitability, frequently in the same patient at different times. Fortunately for the patients, the presenting symptoms of muscle stiffness (myotonia) and muscle weakness (paralysis) are intermittent. The …