Abstract
Na+ homeostasis is a key regulator of cardiac excitation and contraction. The cardiac voltage-gated Na+ channel, NaV1.5, critically controls cell excitability, and altered channel gating has been implicated in both inherited and acquired arrhythmias. Ca2+/calmodulin-dependent protein kinase II (CaMKII), a serine/threonine kinase important in cardiac physiology and disease, phosphorylates NaV1.5 at multiple sites within the first intracellular linker loop to regulate channel gating. Although CaMKII sites on the channel have been identified (S516, T594, S571), the relative role of each of these phospho-sites in channel gating properties remains unclear, whereby both loss-of-function (reduced availability) and gain-of-function (late Na+ current, INaL) effects have been reported. Our review highlights investigating the complex multi-site phospho-regulation of NaV1.5 gating is crucial to understanding the genesis of acquired arrhythmias in heart failure (HF) and CaMKII activated conditions. In addition, the increased Na+ influx accompanying INaL may also indirectly contribute to arrhythmia by promoting Ca2+ overload. While the precise mechanisms of Na+ loading during HF remain unclear, and quantitative analyses of the contribution of INaL are lacking, disrupted Na+ homeostasis is a consistent feature of HF. Computational and experimental observations suggest that both increased diastolic Na+ influx and action potential prolongation due to systolic INaL contribute to disruption of Ca2+ handling in failing hearts. Furthermore, simulations reveal a synergistic interaction between perturbed Na+ fluxes and CaMKII, and confirm recent experimental findings of an arrhythmogenic feedback loop, whereby CaMKII activation is at once a cause and a consequence of Na+ loading.
Highlights
Na+ homeostasis is a key regulator of cardiac excitation and contraction
Na+/Ca2+ exchanger (NCX) is concentrated at the t-tubules, but only a small NCX fraction colocalizes with proteins specific to the dyadic cleft [i.e., L-type Ca2+ channels (LTCCs) and ryanodine receptors (RyRs; Jayasinghe et al, 2009)]
While the increase in INaL may play a role in the observed [Na+]i loading in these transgenic mice (Wagner et al, 2006), we demonstrated that calmodulindependent protein kinase II (CaMKII)-dependent enhancement of INaL is not quantitatively sufficient to account for the [Na+]i elevation observed in heart failure (HF) (Grandi et al, 2007; Wagner et al, 2011; Moreno et al, 2013; Morotti et al, 2014)
Summary
Altered Na+ homeostasis through the mechanisms described above (and in Figure 1) contributes to action potential (AP) and [Ca2+] cycling dysregulation, leading to arrhythmia, metabolic imbalance, remodeling and cell death, and is a hallmark of various cardiac diseases. Wild type or non-phosphorylatable mutant channels (S516A, T594A, S571A) were coexpressed with CaMKIIδC in HEK293 cells and voltage-clamped under pipette conditions to acutely activate CaMKII (with Ca2+ and calmodulin), with or without CaMKII inhibition [by autocamtide-2 inhibitory peptide (AIP); Ashpole et al, 2012]. While no overlap mutations are present, several mutations or polymorphisms have been identified within the I–II loop phosphorylation hot spot through studies of LQTS and BrS patient cohorts. Examination of these mutations may be useful in dissecting out the structure-function relationship of kinase phosphorylation within this region. The mutant NaV1.5 channel displayed a negative shift in inactivation and enhanced entry into inactivation that was not dependent on coexpression of β-subunits
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