Abstract 16237: Striking Electrophysiologic Differences Between Cardiac Sodium Channel Isoforms SCN10A and SCN5A
Introduction: Single nucleotide polymorphisms (SNPs) in the SCN10A locus have been implicated by genome-wide association as modulators of PR and QRS durations. SCN10A encodes the TTX-resistant sodium channel Nav1.8 initially cloned from dorsal root ganglion (DRG) neuronal cells, but more recently identified in heart. Here we compare the functional properties of Nav1.8 and Nav1.5 (encoded by the canonical cardiac sodium channel gene SCN5A) and determine the electrophysiological properties of common SCN10A SNPs (V1073A and L1092P) implicated in variable cardiac conduction.
Methods: Transient transfection of SCN10A with beta subunits in CHO cells generated very small currents. The present studies were conducted in a mouse neuroblastoma-DRG cell line (ND7/23 cells), where robust INa was recorded.
Results: SCN5A transfected in ND7/23 cells displayed INa similar to that seen with β1 subunit coexpression in other cell lines and in myocytes: time to peak (TTP) 1.36±0.04 ms, inactivation time constants 1.3±0.1 ms (τ-fast) and 2.9±0.2 (τ-slow), and peak activation at ~ -30mV. Nav1.8 activated and inactivated much more slowly: time to peak (TTP) 5.6±0.3 ms, inactivation time constants 3.2±0.2 ms (τ-fast) and 18.2±0.9 ms (τ-slow), and peak activation at ~+20mV. Nav1.8 also displayed much larger late currents (INa-L): INa-L at 100-ms post-depolarization was 9.4±1.0% of peak INa versus 0.74±0.09 % for Nav1.5. The two Nav1.8 variants displayed “gain-of-function” with faster activation and inactivation and larger INa-L compared to wild-type Nav1.8 (Table).
Conclusion: These data identify striking functional differences between Nav1.5 and Nav1.8 channels; the functional properties of the cardiac INa will reflect the relative contributions of the two genes. The SCN10A variants display altered function supporting the idea that they are causative for the variable PR and QRS phenotypes identified by GWAS.
- © 2011 by American Heart Association, Inc.