b Voltage-gated sodium channels (Nav) underlie the activity of many excitable cells. Nav channels generate the action potential upstroke by activating in response to a small depolarization of the membrane, resulting in a large influx of Na ions and further membrane depolarization. Dysfuncion in Nav channel activity results in human disease, inluding epilepsy, ataxia, cardiac arrhythmia, and myotoia. In fact, hundreds of variants in SCN5A, the gene encoding Nav1.5, have been linked to human arrhythmia syndromes including long QT type 3, Brugada syndrome, cardiac conduction disease, sinus node disease, and atrial fibrillation. Early studies revealed that variants in key channel domains (e.g., pore or inactivation gate) alter channel biophysical properties to produce abnormal cell excitability. Later, a distinct class of mutations was identified that results in channel dysfunction by altering Nav1.5 interactions with protein partners. Thus, it has become inreasingly clear that localization of Nav to specific memrane domains is a critical determinant of normal cell xcitability. In this issue of HeartRhythm, Lin and coleagues add to our growing appreciation of the link between ion channel location and function in heart. The Nav channel pore-forming alpha-subunit is a single olypeptide with four homologous transmembrane domains DI-DIV) composed of six membrane-spanning alpha-helies (S1–S6). Ten different Nav channel alpha-subunits are resent in mammals, each with specific biophysical and xpression signatures. For example, Nav1.5, the primary av channel expressed in heart, is resistant to the neurotoxin etrodotoxin (TTX) with a relatively low affinity in the icromolar range compared with neuronal TTX-sensitive av (affinity in the nM range). Furthermore, Nav1.5 gates