ABSTRACT

In their Nobel Prize-winning formulation of the squid giant axon, Hudgkin and Hulxey [1] showed how quantitative models could be applied to describe how ion currents shaped electrical signaling. In the Hodgkin and Huxley models, parameters for activation and inactivation were t from experimentally observed electrophysiological data. With the advent of molecular biology in the late 1980s, ion channels were cloned, and fulllength sequences become known for many ion channels [2-5]. It was a natural question to ask how sequence variation in ion channels was linked to variation in parameters that described their electrical properties. With the introduction of sitedirected mutagenesis and the ability to express ion channels in exogenous systems such as Xenopus oocytes [6], the eect of changes in sequence could be directly measured. is approach of introducing variants into a channel sequence and observing the results for channel function has had many successes in a wide variety of channels and has produced a detailed understanding of how sequence variation can constrain channel function. For example, in Shaker potassium channels, site-directed mutagenesis demonstrated that inactivation was tied to the amino-terminus region [7]. In the CFTR channel, distinct mutations associated with loss of channel function were determined to be causative of most types of cystic brosis [8].