Na v 1.5 regulates intrinsic cardiac neuronal excitability and expands the cellular basis of SCN5A channelopathies
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Background
Loss- and gain-of-function variants in SCN5A , encoding the cardiac sodium channel Na v 1.5, are major causes of inherited cardiac channelopathies. Their pathophysiology has almost exclusively been attributed to altered cardiomyocyte excitability and cardiac conduction. However, growing evidence indicates that autonomic dysfunction contributes to these disorders, raising the possibility that Na v 1.5 dysfunction may also affect the intrinsic cardiac nervous system.
Objectives
We investigated whether Na v 1.5 is functionally expressed in murine intrinsic cardiac neurons and evaluated its contribution to neuronal excitability.
Methods
Scn5a expression was investigated by digital PCR and immunocytochemistry in isolated murine intracardiac neurons. Whole-cell patch-clamp recordings were used to characterize sodium currents and action potential properties in wild-type and Scn5a +/− mice.
Results
Scn5a transcripts and Na v 1.5 protein were detected in intrinsic cardiac neurons. Voltage-clamp recordings identified a tetrodotoxin-resistant sodium current accounting for approximately 8% of the total sodium current and displaying pharmacological and biophysical properties consistent with Na v 1.5. Activation and inactivation analyses indicated that Na v 1.5 is the predominant sodium conductance available at most polarized membrane potentials. Accordingly, Scn5a haploinsufficiency selectively altered action potential threshold, maximal upstroke velocity, overshoot and duration in neurons resting below −60 mV, whereas more depolarized neurons were essentially unaffected. No structural or neurochemical remodeling of intrinsic cardiac ganglia was detected.
Conclusion
Na v 1.5 is a functional determinant of intrinsic cardiac neuronal excitability. These findings identify the intrinsic cardiac nervous system as a new cellular target of SCN5A dysfunction and suggest that inherited cardiac sodium channelopathies could involve alterations in both myocardial and intrinsic neuronal electrophysiology.
