Review articleChannelopathies from mutations in the cardiac sodium channel protein complex
Section snippets
INa in heart: Excitability, arrhythmogenesis, and sodium–calcium homeostasis
Sodium current (INa) underlies excitability in cardiac ventricular and atrial myocytes and also in specialized conduction tissue including Purkinje cells. Peak INa is a large inward current responsible for rapid upstroke of the action potential (phase 0) and for conduction in working myocardium. The INa flowing just milliseconds after the peak, here called “early INa”, decays rapidly but helps sustain the initial plateau (phase 1) during activation of the transient outward potassium current (Ito
Arrhythmia syndromes associated with mutations in SCCPs
This review focuses on those SCCPs for which putative mutations have been identified in arrhythmia patients and for which dysfunctional INa supports a plausible arrhythmogenic mechanism through either gain of function, loss of function, or both. Many of these SCCPs interact with other ion channels and may have multiple roles in cardiac myocytes, and thus the mutations may have additional arrhythmogenic mechanisms in addition to INa dysfunction.
Other cardiac SCCPs
Many cardiac SCCPs have been identified that modulate cardiac INa, but mutations in these proteins have yet to be discovered in patients with inherited arrhythmias of unknown origin. These SCCPs (listed in Table 2, with additional possible SCCPs discussed in the online supplement) are candidate genes for SCN5A channelopathies.
Comments and conclusions
Channelopathies caused by mutations in SCCPs, although relatively rare clinically, are “natural” experiments that give insight into the structure function of SCCs. For example, a function for GPD1L was completely unknown until associated with SCN5A and BrS [82]. Conversely, work associating SNTA1 with SCN5A [67] led to the discovery of LQT12 [87] and further definition of a particular SCC (Fig. 1A,D). Genotype-negative inherited arrhythmia patients (patients for which the causative gene and
Disclosures
None.
Conflict of interest
The authors declare no conflict of interest.
Acknowledgment
This work was supported by the NIH NHLBI HL71092 and T32 HL07936.
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2021, StructureCitation Excerpt :CaMN extending toward the IG may assist in capture of (Ca2+)4-CaM during transient release from the IQ motif. Alternatively, Ca2+ binding to CaM may promote bridging an IQ motif and a distant NaV site, as proposed for NaV1.4 (Young and Caldwell, 2005) and NaV1.5 (Adsit et al., 2013), and described for CaV1.2 and CaV1.3 (Tippens and Lee, 2007; Dick et al., 2008; Tadross et al., 2008; Liu and Vogel, 2012). There are multiple parallels in regulation of CaV and NaV channels (Ben-Johny et al., 2014b), but they differ considerably in affinity for apo CaM (Evans et al., 2011; Findeisen et al., 2013).
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2016, Current Topics in MembranesCitation Excerpt :In a number of families with BrS or idiopathic ventricular fibrillation, the R1232W and T1620M mutants of human cardiac Nav1.5 show loss of channel function. Since then, many more SCN5A mutations have been found to be responsible for different syndromes with both gain and loss of channel function (Adsit, Vaidyanathan, Galler, Kyle, & Makielski, 2013; Amin, Asghari-Roodsari, & Tan, 2010; Remme, 2013; Ruan, Liu, & Priori, 2009; Zimmer & Surber, 2008). As shown in Fig. 2B, gain-of-function mutations of SCN5A can cause LQT3 and possibly atrial fibrillation (AFib).