{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSCN10A encodes the tetrodotoxin‐resistant sodium channel Nav1.8, which has emerged as a key modulator of cardiac electrical conduction. In several genome‐wide association studies, common SCN10A variants have been robustly linked with altered PR interval and QRS duration, as well as with increased susceptibility to conduction abnormalities and life‐threatening arrhythmias including Brugada syndrome, atrial fibrillation, and heart block. In addition, enhancer elements within the SCN10A locus appear to regulate expression of nearby cardiac sodium channel genes (such as SCN5A), suggesting that SCN10A impacts cardiac electrophysiology both directly through its channel properties and indirectly via transcriptional control. These observations indicate that inherited genetic variation in SCN10A can substantially modulate cardiac conduction and predispose to arrhythmogenic conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn peripheral sensory neurons, Nav1.8 is predominantly expressed in small‐diameter dorsal root ganglion cells and plays a central role in initiating and sustaining action potentials. Functional studies have revealed that gain‐of‐function mutations in SCN10A alter channel gating—through mechanisms such as enhanced ramp and resurgent currents or trafficking defects—which in turn promote hyperexcitability of nociceptors and are associated with painful small‐fiber neuropathy and other neuropathic pain syndromes. Moreover, differences in biophysical properties between human and rodent Nav1.8 further underscore its importance in setting abnormal pain thresholds and suggest that modulation of Nav1.8 activity may be a valuable strategy for pain management."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical roles in regulating cardiac conduction and nociceptive signaling, SCN10A—and consequently Nav1.8—also contributes to diverse cellular functions in other tissues. Evidence of its expression in cardiomyocytes (and even in human sperm cells) coupled with discoveries of regulatory mechanisms such as endoplasmic reticulum retention signals, calmodulin binding, and modulation by Ca²⁺/calmodulin-dependent protein kinase II highlights a complex molecular network that governs channel density, trafficking, and activity. Together, these findings not only deepen our understanding of the multifaceted roles of SCN10A in both excitable cardiac and peripheral tissues but also suggest that targeted modulation of Nav1.8 may hold promise as a therapeutic strategy for arrhythmias, neuropathic pain, and potentially other conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "45"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Arne Pfeufer, Charlotte van Noord, Kristin D Marciante, et al. 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