How insensitive … How a mutation in the SCN5A voltage sensor leads to clinical arrhythmia

Abstract

t i g a c m w a Earlier this year (2012), one of the fathers of electrohysiology passed away at the age of 94. Sir Andrew Huxley, along with his research partner Sir Alan Hodgkin, first described in the 1940s and 1950s the electrical underpinnings of nerve conduction by using a squid giant axon model. Theirs was the first description of the critical importance of sodium and potassium transmembrane flux in the conduction of electrical impulses in biologic tissues. They even postulated the presence of discrete carriers of sodium and potassium current within the membrane, now well understood to be transmembrane ion channels. Hodgkin and Huxley, along with John Eccles, were awarded the Nobel Prize in Physiology or Medicine for their work. Decades later, Neher and Sakmann performed the first single-channel patchclamp experiments that gave direct evidence of the existence of discrete membrane entities that carry specific ionic currents, including sodium. Subsequently, basic science electrophysiologists were able to deduce much of the functional details of these putative ion channels, including their electrophysiologic characteristics, and even their likely molecular underpinnings, merely based on the clever observation of their behavior both in the native state and in response to electrical and chemical perturbations in the laboratory. With the development of molecular cloning and sequencing techniques, the genetic code for many ion channels, including potassium, sodium, and calcium channels, was revealed. One of the more exciting observations was that any common structural themes were seen across different lasses of ion channels. Among voltage-gated channels, a ommon theme became clear: the fourth transmembrane egment (S4) contained, in addition to a string of hydrohobic amino acids that enabled it to reside within the ellular membrane, charged amino acids—specifically argiine—repeated every 3 amino acids several times. It was mmediately postulated that this motif acted as a “voltage ensor,” residing in the hydrophobic cellular membrane, ble to respond to the changes in membrane potential seen