Sodium channels are principal molecular determinants responsible for myocardial 
conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a 
fundamental role in the coupling of cardiac myocyte excitation and contraction, 
yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel 
function have yet to be identified. Here we show that calmodulin (CaM), a 
ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of 
the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding 
interaction significantly enhances slow inactivation-a channel-gating process 
linked to life-threatening idiopathic ventricular arrhythmias. Mutations 
targeted to the IQ domain disrupted CaM binding and eliminated 
Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM 
were restored by intracellular application of a peptide modelled after the IQ 
domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 
function in a manner characteristic of the Brugada arrhythmia syndrome, but at 
the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a 
clinically benign (arrhythmia free) phenotype.