Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms

Abstract

The cardiac sodium channel NaV1.5, encoded by the SCN5A gene, is responsible for the fast upstroke of the action potential. Mutations in SCN5A may cause sodium channel dysfunction by decreasing peak sodium current, which slows conduction and facilitates reentry-based arrhythmias, and by enhancing late sodium current, which prolongs the action potential and sets the stage for early afterdepolarization and arrhythmias. Yet, some NaV1.5-related disorders, in particular structural abnormalities, cannot be directly or solely explained on the basis of defective NaV1.5 expression or biophysics. An emerging concept that may explain the large disease spectrum associated with SCN5A mutations centres around the multifunctionality of the NaV1.5 complex. In this alternative view, alterations in NaV1.5 affect processes that are independent of its canonical ion-conducting role. We here propose a novel classification of NaV1.5 (dys)function, categorized into (i) direct ionic effects of sodium influx through NaV1.5 on membrane potential and consequent action potential generation, (ii) indirect ionic effects of sodium influx on intracellular homeostasis and signalling, and (iii) non-ionic effects of NaV1.5, independent of sodium influx, through interactions with macromolecular complexes within the different microdomains of the cardiomyocyte. These indirect ionic and non-ionic processes may, acting alone or in concert, contribute significantly to arrhythmogenesis. Hence, further exploration of these multifunctional effects of NaV1.5 is essential for the development of novel preventive and therapeutic strategies.

Keywords: SCN5A; Mechanisms; NaV1.5; Sodium channelopathies; Therapies.

Figure 1

The cardiac voltage-gated sodium channel Na_V1.5. Upper panel: unfolded Na_V1.5 protein at the cardiomyocyte plasma membrane featuring four domains (I, II, III, IV) each containing six segments (S1–S6). The charged segment S4 is represented in green. Lower left panel: folded Na_V1.5 at the cardiomyocyte plasma membrane. The rapid inward sodium current depolarizes the cell membrane. Lower right panel: relation between the sodium current and the upstroke of the action potential (green segments).

Figure 2

Regional and subcellular distribution of SCN5A/Na_V1.5 in the heart and cardiomyocyte. Left panel: schematic representation of a heart showing the expression level of SCN5A in the different compartments. Expression of SCN5A is highest in the AV bundle, His bundle, and RBB and LBB (dark green). SCN5A is broadly expressed in RA and LA and RV and LV with an epi/endo gradient in the ventricles. SCN5A is absent from the central SAN and AVN. Right panel: schematic representation of the localization of Na_V1.5 with specific regional partner proteins in the microdomains of the cardiomyocyte: ID, LM, and T-tubules. The sodium current generated at the ID is larger than the sodium current generated at the LM. LA, left atria; LBB, left bundle branch; LV, left ventricle; RA, right atria; RBB, right bundle branch; RV, right ventricle; SAN, sinoatrial node.

Figure 3

Schematic representation of the arrhythmogenic consequences of reduced peak sodium current (peak I_Na; left) and increased late sodium current (late I_Na; right). APD, action potential duration; [Ca²⁺]_i, intracellular calcium concentration; [Na⁺]_i, intracellular sodium concentration. Redrawn from Remme and Wilde with permission.

Figure 4

Novel classification of Na_V1.5 (dys)function. The direct ionic function controls excitability by modification of membrane potential and initiation of AP. The indirect ionic function regulates calcium levels and downstream calcium signalling. The non-ionic function relies on the integrity of region-specific macromolecular complexes to control cell adhesion, cell–cell communication, signalling (other than calcium), myocardium architecture (extracellular matrix), and developmental aspects. AP, action potentials.