The sodium channel Na_X: Possible player in excitation–contraction coupling

The sodium channel Na_X (encoded by the SCN7A gene) was originally identified in the heart and skeletal muscle and is structurally similar to the other voltage-gated sodium channels but does not appear to be voltage gated. Although Na_X is expressed at high levels in cardiac and skeletal muscle, little information exists on the function of Na_X in these tissues. Transcriptional profiling of ion channels in the heart in a subset of patients with Brugada syndrome revealed an inverse relationship between the expression of Na_X and Na_V1.5 suggesting that, in cardiac myocytes, the expression of these channels may be linked. We propose that Na_X plays a role in excitation–contraction coupling based on our experimental observations. Here we show that in cardiac myocytes, Na_X is expressed in a striated pattern on the sarcolemma in regions corresponding to the sarcomeric M-line. Knocking down Na_X expression decreased Na_V1.5 mRNA and protein and reduced the inward sodium current (I_Na+) following cell depolarization. When the expression of Na_V1.5 was knocked down, ~85% of the I_Na+ was reduced consistent with the observations that Na_V1.5 is the main voltage-gated sodium channel in cardiac muscle and that Na_X likely does not directly participate in mediating the I_Na+ following depolarization. Silencing Na_V1.5 expression led to significant upregulation of Na_X mRNA. Similar to Na_V1.5, Na_X protein levels were rapidly downregulated when the intracellular [Ca²⁺] was increased either by CaCl₂ or caffeine. These data suggest that a relationship exists between Na_X and Na_V1.5 and that Na_X may play a role in excitation–contraction coupling.