The cardiac sodium channel from function to dysfunction

Activation of the voltage-gated sodium channel underlies the upstroke of the cardiac action potential, its subsequent inactivation being fundamental to the establishment of a refractory period. Thus, the sodium channel is central to the orderly conduction of electrical activity through the heart and represents an important target for anti-arrhythmic drugs. Biophysical and structural studies on mutations of the cardiac sodium channel known to cause arrhythmia have provided insight both into the structural basis of channel function and into the physiological role of the channel. A picture is emerging of sodium channels existing in distinct subdomains at the surface sarcolemma and at the intercalated discs, differentially regulated according to the ancillary proteins and beta-subunits. Three papers in this issue of The Journal of Physiology explore the role NaV1.5 plays in cardiac physiology and pathology. NaV1.5 is a complex multimeric protein heteromer with multiple domains involved in its function. The exact subunit composition of the NaV1.5 channel protein complex itself is something of relevant physiological research, with tissue expression varying by organ and within the organ (Salvage et al., 2023). The various beta subunits that are part of the NaV1.5 channel allow NaV1.5 channel isomers that are differentially expressed throughout the myocardium – though the precise distribution and perhaps even function of these subunits when combined to form the full protein channel can vary depending on the organism (Salvage et al., 2023), with obvious potential consequences for physiology and pathology. Different isomers of NaV1.5 are present on the sarcolemmal surface and are localised in subcellular microdomains – either at the lateral membrane (Eichel et al., 2016) or at the cell junction's intercalated discs (Agullo-Pascual et al., 2014). The various isomers contain different beta subunits that affect the ion channel current-carrying capacity and action potential waveform and duration. However, the effect of incorporating each beta subunit into the NaV1.5 channel has sometimes yielded contradictory results (Salvage et al., 2023). The role of NaV1.5 as part of larger macromolecular complexes at the intercalated disc and lateral membrane, as well as in the maintenance of healthy cell–cell interactions including fibroblasts is also indicated from the SCN5A−/− mouse model of the Brugada syndrome, where knockout results in disruption of the normal tissue architecture with extensive fibrosis (Jeevaratnam et al., 2012). Evidence in mouse models reveals that NaV1.5 dysfunction affects myocardial structural integrity, impacting cell adhesion (Marchal cell surface caveolae are reduced in heart failure and increased expression increases sodium current density (Marchal Valdivia et al., 2005). The NaV1.5 channel also profoundly affects Ca2+ homeostasis. This is true in physiological conditions as well as in disease states, and the subunits that form the channel may be particularly important in how this interaction occurs and in its effects. The mechanism of muscle contraction known as calcium-induced calcium release relies on precise spatial localisation of an array of proteins including the Nav1.5 channel, L-type calcium channels and the ryonadine receptor (RyR) to the t-tubule in the sarcolemma (MacLeod, 2023; Marchal Shah et al., 2006). Using isolated protein fragments, a number of biophysical studies have demonstrated that Site A and Site B of the Nav DIII–DIV linker domain bind to the C- and N-lobes of Ca2+-calmodulin, respectively. This interaction does not occur with the C- or N-lobes of apo-calmodulin (Ca2+-free calmodulin) (Johnson et al., 2018; Sarhan et al., 2012). This differential binding between calcium-high and calcium-low states is an obvious calcium sensor mechanism to exert signalling control over NaV1.5. Thus, NaV1.5 possesses potentially regulatory binding sites for Ca2+ and/or the Ca2+ sensor calmodulin in their inactivating the III–IV linker and C-terminal domains (CTDs), where mutations are associated with a range of skeletal and cardiac muscle diseases such as hypokalaemic periodic paralysis (Salvage et al., 2021). In vitro conventional patch-clamp experiments investigating Ca2+-dependent Nav1.4 and Nav1.5 current modulation have demonstrated a range of effects including reductions in peak sodium current (Casini et al., 2009; Yoder et al., 2019). These experiments were performed in heterologous tsA201, HEK293 and CHO expression systems. However, native skeletal and cardiac myocytes also show acute Ca2+-dependent INa modulation. In murine skeletal muscle, acute RyR2 activation by the exchange protein directly activated by cAMP (Epac) by the activator 8-(4-chlorophenylthio)adenosine-3′,5′-cyclic monophosphate (8-CPT, 1 μM), reduced maximum INa whilst leaving V1/2 values unchanged. This effect was nullified by the RyR inhibitor dantrolene (Matthews et al., 2019). Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations treated with 8-CPT correspondingly demonstrated reduced maximum atrial and ventricular (dV/dt)max (Valli et al., 2018). Conduction velocity decreased even when measured by action potential latency, while action potential duration and refractory periods were unchanged. Arrhythmic propensity was also affected, with more arrhythmic events following rapid pacing or extrasystolic stimuli (Li et al., 2017). It is clear that the NaV1.5 channel is a complex cellular protein that lies at the heart of a web of interacting signalling cascades and ionic currents. The complex spatial and temporal localisation, trafficking, and functional and structural isomerism is beginning to be unravelled to not only allow deeper insights in the physiological function but also tantalisingly may offer yet more targets for therapeutic intervention. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. No competing interests is declared. Sole author. None.