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

Abstract

The sodium channel NaX (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 NaX is expressed at high levels in cardiac and skeletal muscle, little information exists on the function of NaX 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 NaX and NaV1.5 suggesting that, in cardiac myocytes, the expression of these channels may be linked. We propose that NaX plays a role in excitation–contraction coupling based on our experimental observations. Here we show that in cardiac myocytes, NaX is expressed in a striated pattern on the sarcolemma in regions corresponding to the sarcomeric M‐line. Knocking down NaX expression decreased NaV1.5 mRNA and protein and reduced the inward sodium current (INa+) following cell depolarization. When the expression of NaV1.5 was knocked down, ~85% of the INa+ was reduced consistent with the observations that NaV1.5 is the main voltage‐gated sodium channel in cardiac muscle and that NaX likely does not directly participate in mediating the INa+ following depolarization. Silencing NaV1.5 expression led to significant upregulation of NaX mRNA. Similar to NaV1.5, NaX protein levels were rapidly downregulated when the intracellular [Ca2+] was increased either by CaCl2 or caffeine. These data suggest that a relationship exists between NaX and NaV1.5 and that NaX may play a role in excitation–contraction coupling.

Impact of Dietary Factors on Brugada Syndrome and Long QT Syndrome

“…Furthermore, atrial and ventricular arrhythmias can also be induced by caffeine, which is able to interfere with calcium homeostasis [ 115 , 119 ] by increasing intracellular calcium concentration [ 115 ]. Indeed, it was demonstrated that caffeine is able to stimulate calcium release from the sarcoplasmic reticulum [ 120 ], and calcium imbalances, particularly sarcoplasmic reticulum calcium stores, may be altered in BrS [ 121 , 122 , 123 ]. A 24-year-old male developed arrhythmias and collapsed after the ingestion, for the first time, of a small quantity of an energy drink combined with alcohol; specifically, the drink contained 80 mg of caffeine and 1000 mg of taurine, plus Vodka.…”

Caffeine Consumption Influences Lidocaine Action via Pain-Related Voltage-Gated Sodium Channels: An In Vivo Animal Study

“…Sarbjit-Singh et al [ 24 ] found that caffeine may inactivate the Nav1.4 channel in murine skeletal muscle fibers, leading to sodium current inhibition. Moreover, levels of the Nav1.5 and NaX proteins were downregulated by caffeine, changes that were associated with increased intracellular calcium concentrations in cardiac myocytes [ 25 ]. On the other hand, the main transducer in thermal (heat) pain sensory neurons is transient receptor potential cation channel subfamily V member 1 (TRPV1), where temperature gradually increases its activity [ 13 ].…”