Slow inactivation

Abstract

Skeletal muscle membrane excitability resides on a razor’s edge. Increasing excitability leads to myotonia. Reducing excitability can lead to paralysis due to membrane inexcitability. By complexly altering membrane excitability, channelopathies can produce phenotypes that are characterized by both hyperexcitability and paralysis. Detailed physiologic studies can sometimes explain the complex phenotypes produced by specific channelopathies. In this issue of Neurology ®, Webb and Cannon1 provide a cogent explanation for the genesis of a phenotype of myotonia at warm temperature and cold-induced paralysis that is associated with the P1158S mutation of the skeletal muscle sodium channel, NaV1.4. Skeletal muscle channelopathies are fascinating because they illuminate the connection between basic physiology and clinical neurology. The channelopathies are natural experiments that enable us to explore how altering the function of a channel changes membrane excitability. Nobel laureates Hodgkin and Huxley2 opened the modern age of membrane physiology more than a half-century ago through a series of elegant experiments that demonstrated that the action potential in the giant axon of a squid was produced by an interplay between voltage-gated …