Action potentials in postganglionic sympathetic nerves depend on NaV1.7

Nerve fibres of the peripheral and the central nervous system convey information via action potential sequences. In nerve fibres, activation of voltage-dependent sodium (NaV) channels is required to generate and conduct action potentials. In humans, 10 homologous genes encode for the pore-forming NaV channel α-subunits, leading to functionally and pharmacologically distinct ion channels that differ with regard to their tissue distribution. The α-subunit of NaV1.7 is encoded by SCN9A, and this ion channel is present in peripheral nociceptive neurons (Dormer et al., 2023). Missense NaV1.7 mutations reduce and gain-of-function NaV1.7 mutations increase pain sensitivity in affected patients. Based, in part, on such clinical observations, selective NaV1.7 blockers have been developed as a potential new class of analgesics (Dormer et al., 2023). In addition to nociceptive neurons, sympathetic postganglionic neurons have long been known to express NaV1.7 (Morinville et al., 2007). However, the precise contribution of NaV1.7 to action potential generation and conduction in sympathetic neurons was less well understood. Beyond the advancement of basic physiological knowledge in this area, clarification of the contribution of specific ion channels to the excitability of sympathetic neurons is of clinical importance because elevated sympathetic nerve activity is part of the pathogenesis of many diseases. In this issue of The Journal of Physiology, Kim et al. (2024) provide data on NaV1.7 mRNA expression in guinea pig stellate ganglia and the contribution of NaV1.7 to sympathetic nerve fibre-induced vasoconstriction in guinea pig and human large conduit vessels. By applying single-cell PCR, the authors showed that NaV1.7 mRNA was present in almost all stellate ganglion neurons investigated. This was not the case for other tetrodotoxin-sensitive sodium channels generally present in peripheral neurons. The authors recorded multifibre compound action potentials in postganglionic sympathetic nerves and vascular tension in response to electrical field stimulation of sympathetic nerve fibres in the absence or presence of selective NaV1.7 blockers to establish the contribution of NaV1.7 to action potential conduction. They demonstrated a large reduction of compound action potential amplitude in postganglionic sympathetic nerve fibres in response to pharmacological NaV1.7 blockade. Aortic and pulmonary artery segment vasoconstrictor responses to electrical field stimulation were largely inhibited but not abolished by selective NaV1.7 blockers. The data indicate that in postganglionic sympathetic nerve fibres, action potential conduction depends to a large extent on NaV1.7. Sympathetic fibre action potential propagation was not fully prevented by NaV1.7 channel blockade. Thus, the data suggest that other voltage-dependent sodium channels contribute to action potential conduction in postganglionic sympathetic nerves. Action potential generation follows the 'all or nothing' principle, i.e. when their threshold is exceeded, individual action potentials do not vary significantly in amplitude. Thus, the contribution of NaV1.7 to action potential propagation appears to differ between individual nerve fibres. Future research in this area might identify individual NaV1.7-dependent and -independent nerve fibres within a peripheral postganglionic sympathetic nerve. Furthermore, it could be established to what extent NaV1.7 contributes to sympathetic fibre action potential propagation to small arteries and arterioles that participate in the regulation of total peripheral resistance and arterial pressure, in addition to other target organs of the sympathetic nervous system. Such data would facilitate the understanding of side effects of NaV1.7 blocker treatment, such as arterial hypotension (Rothenberg et al., 2019), and provide a basis for the potential use of NaV1.7 blockers to lower arterial pressure when desired. The hypothesis could be tested of whether alterations in NaV1.7 expression and function contribute to elevated sympathetic activity in frequently occurring pathological conditions, such as cardiovascular and renal diseases. This would provide a scientific basis for the potential application of NaV1.7 blockers to treat dysautonomias and cardiovascular diseases characterized by heightened activity of the sympathetic nervous system (Grassi & Drager, 2024). NaV1.7 blockers could be of use to perform a graded and reversible peripheral sympathetic denervation to treat arterial hypertension, chronic heart failure and other pathological states in which elevated sympathetic activity is part of the pathogenesis. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. None. Sole author. None. Open access funding enabled and organized by Projekt DEAL.