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Mutations in the  SCN5A  gene, encoding the cardiac voltage-gated sodium channel Na V 1.5, are associated with inherited cardiac arrhythmia and conduction disease. Ca 2+ -dependent mechanisms and the involvement of β-subunit (Na V β) in Na V 1.5 regulation are not fully understood. A patient with severe sinus-bradycardia and cardiac conduction-disease was genetically evaluated and compound heterozygosity in the  SCN5A  gene was found. Mutations were identified in the cytoplasmic DIII-IV linker (K1493del) and the C-terminus (A1924T) of Na V 1.5, both are putative CaM-binding domains. These mutants were functionally studied in human embryonic kidney (HEK) cells and HL-1 cells using whole-cell patch clamp technique. Calmodulin (CaM) interaction and cell-surface expression of heterologously expressed Na V 1.5 mutants were studied by pull-down and biotinylation assays. The mutation K1493del rendered Na V 1.5 non-conductive. Na V 1.5 K1493del  altered the gating properties of co-expressed functional Na V 1.5, in a Ca 2+  and Na V β1-dependent manner. Na V 1.5 A1924T  impaired Na V β1-dependent gating regulation. Ca 2+ -dependent CaM-interaction with Na V 1.5 was blunted in Na V 1.5 K1493del . Electrical charge substitution at position 1493 did not affect CaM-interaction and channel functionality. Arrhythmia and conduction-disease -associated mutations revealed Ca 2+ -dependent gating regulation of Na V 1.5 channels. Our results highlight the role of Na V 1.5 DIII-IV linker in the CaM-binding complex and channel function, and suggest that the Ca 2+ -sensing machinery of Na V 1.5 involves Na V β1.

Mutations in NaV1.5 Reveal Calcium-Calmodulin Regulation of Sodium Channel