Na+ Channel I–II Loop Mediates Parallel Genetic and Phosphorylation-Dependent Gating Changes
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In this issue of Circulation, Koval et al1 show that 2 arrhythmogenic human cardiac Na+ channel (hNaV1.5) variants mimic the altered channel gating effects induced by Ca2+-calmodulin–dependent protein kinase (CaMKII). They also show that phosphorylation of an adjacent CaMKII target site on NaV1.5 is enhanced in human heart failure (HF) samples and in the border zone of postinfarcted canine hearts.
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The cardiac Na+ channel, NaV1.5, is responsible for inward Na+ current (INa) that drives the cardiac action potential (AP) upstroke and electrical impulse propagation.2 Genetic variants of the SCN5A gene encoding NaV1.5 are associated with long QT syndrome-3 (LQTs; gain of function), Brugada syndrome (BRs; loss of function), conduction system disease, sudden infant death syndrome, sick sinus syndrome, and dilated cardiomyopathy.3,4 These inherited channelopathies have been tremendously important to our understanding of normal NaV1.5 function and arrhythmia mechanisms. However, acquired forms of altered NaV1.5 function attributable to posttranslational modification (eg, phosphorylation or oxidation) may have pathophysiological consequences during ischemia/reperfusion or HF and thus reach a larger patient population. Indeed, half of all HF deaths are sudden and presumed to be attributable to lethal ventricular arrhythmias.5,6
The pore forming α subunit (NaV1.5; ≈220 Kd predicted MW) has 4 homologous domains (I–IV) with 6 transmembrane segments each (S1–S6; Figure 1), is glycosylated, and has auxiliary regulatory β subunits (β1–β4; ≈30–35 Kd).7 The S5–S6 linker includes the P-loops or pore region, the 4 S4 segments serve as voltage sensors (involved in activation gating), whereas an IFM motif in the DIII–IV linker is important for fast inactivation gating. Importantly, NaV1.5 forms a macromolecular complex with interacting proteins that …