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A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.

ABSTRACT: The resurgent sodium current (I_NaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, I_NaR is thought to drive high rates of repetitive neuronal firing. However, I_NaR is often studied in combination with the persistent or non-inactivating portion of sodium currents (I_NaP). We used dynamic clamp to test how I_NaR and I_NaP individually affect repetitive firing in adult cerebellar Purkinje neurons. We learned I_NaR does not scale repetitive firing rates due to its rapid decay at subthreshold voltages, and that subthreshold I_NaP is critical in regulating neuronal firing rate. Adjustments to the Nav conductance model used in these studies revealed I_NaP and I_NaR can be inversely scaled by adjusting occupancy in the slow inactivated kinetic state. Together with additional dynamic clamp experiments, these data suggest the regulation of sodium channel slow inactivation can fine-tune I_NaP and Purkinje neuron repetitive firing rates.

SUBMITTER: Brown SP

PROVIDER: S-EPMC10769191 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.

Brown Samuel P SP Lawson Ryan J RJ Moreno Jonathan D JD Ransdell Joseph L JL

bioRxiv : the preprint server for biology 20240601

The resurgent sodium current (INaR) activates on membrane repolarization, such as during the downstroke of neuronal action potentials. Due to its unique activation properties, INaR is thought to drive high rates of repetitive neuronal firing. However, INaR is often studied in combination with the persistent or non-inactivating portion of sodium currents (INaP). We used dynamic clamp to test how INaR and INaP individually affect re ...[more]

PMID: 38187680

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Project description:Vestibular afferent neurons occur as two populations with differences in spike timing regularity that are independent of rate. The more excitable regular afferents have lower current thresholds and sustained spiking responses to injected currents, while irregular afferent neurons have higher thresholds and transient responses. Differences in expression of low-voltage-activated potassium (KLV) channels are emphasized in models of spiking regularity and excitability in these neurons, leaving open the potential contributions of the voltage-gated sodium (NaV) channels responsible for the spike upstroke. We investigated the impact of different NaV current modes (transient, persistent, and resurgent) with whole-cell patch clamp experiments in mouse vestibular ganglion neurons (VGNs), the cultured and dissociated cell bodies of afferents. All VGNs had transient NaV current, many had a small persistent (non-inactivating) NaV current, and a few had resurgent current, which flows after the spike when NaV channels that were blocked are unblocked. A known NaV1.6 channel blocker decreased spike rate and altered spike waveforms in both sustained and transient VGNs and affected all three modes of NaV current. A NaV channel agonist enhanced persistent current and increased spike rate and regularity. We hypothesized that persistent and resurgent currents have different effects on sustained (regular) VGNs vs. transient (irregular) VGNs. Lacking blockers specific for the different current modes, we used modeling to isolate their effects on spiking of simulated transient and sustained VGNs, driven by simulated current steps and noisy trains of simulated EPSCs. In all simulated neurons, increasing transient NaV current increased spike rate and rate-independent regularity. In simulated sustained VGNs, adding persistent current increased both rate and rate-independent regularity, while adding resurgent current had limited impact. In transient VGNs, adding persistent current had little impact, while adding resurgent current increased both rate and rate-independent irregularity by enhancing sensitivity to synaptic noise. These experiments show that the small NaV current modes may enhance the differentiation of afferent populations, with persistent currents selectively making regular afferents more regular and resurgent currents selectively making irregular afferents more irregular.

Project description:BACKGROUND: Gain-of-function mutations of the nociceptive voltage-gated sodium channel Nav1.7 lead to inherited pain syndromes, such as paroxysmal extreme pain disorder (PEPD). One characteristic of these mutations is slowed fast-inactivation kinetics, which may give rise to resurgent sodium currents. It is long known that toxins from Anemonia sulcata, such as ATX-II, slow fast inactivation and skin contact for example during diving leads to various symptoms such as pain and itch. Here, we investigated if ATX-II induces resurgent currents in sensory neurons of the dorsal root ganglion (DRGs) and how this may translate into human sensations. RESULTS: In large A-fiber related DRGs ATX-II (5 nM) enhances persistent and resurgent sodium currents, but failed to do so in small C-fiber linked DRGs when investigated using the whole-cell patch-clamp technique. Resurgent currents are thought to depend on the presence of the sodium channel ?4-subunit. Using RT-qPCR experiments, we show that small DRGs express significantly less ?4 mRNA than large sensory neurons. With the ?4-C-terminus peptide in the pipette solution, it was possible to evoke resurgent currents in small DRGs and in Nav1.7 or Nav1.6 expressing HEK293/N1E115 cells, which were enhanced by the presence of extracellular ATX-II. When injected into the skin of healthy volunteers, ATX-II induces painful and itch-like sensations which were abolished by mechanical nerve block. Increase in superficial blood flow of the skin, measured by Laser doppler imaging is limited to the injection site, so no axon reflex erythema as a correlate for C-fiber activation was detected. CONCLUSION: ATX-II enhances persistent and resurgent sodium currents in large diameter DRGs, whereas small DRGs depend on the addition of ?4-peptide to the pipette recording solution for ATX-II to affect resurgent currents. Mechanical A-fiber blockade abolishes all ATX-II effects in human skin (e.g. painful and itch-like paraesthesias), suggesting that it mediates its effects mainly via activation of A-fibers.

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A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.

Publications

A Reinterpretation of the Relationship Between Persistent and Resurgent Sodium Currents.

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