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Role of Na_V1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.

ABSTRACT: Inspiration is the inexorable active phase of breathing. The brainstem pre-Bötzinger complex (preBötC) gives rise to inspiratory neural rhythm, but its underlying cellular and ionic bases remain unclear. The long-standing "pacemaker hypothesis" posits that the persistent Na⁺ current (I_NaP) that gives rise to bursting-pacemaker properties in preBötC interneurons is essential for rhythmogenesis. We tested the pacemaker hypothesis by conditionally knocking out and knocking down the Scn8a (Na_v1.6 [voltage-gated sodium channel 1.6]) gene in core rhythmogenic preBötC neurons. Deleting Scn8a substantially decreases the I_NaP and abolishes bursting-pacemaker activity, which slows inspiratory rhythm in vitro and negatively impacts the postnatal development of ventilation. Diminishing Scn8a via genetic interference has no impact on breathing in adult mice. We argue that the Scn8a-mediated I_NaP is not obligatory but that it influences the development and rhythmic function of the preBötC. The ubiquity of the I_NaP in respiratory brainstem interneurons could underlie breathing-related behaviors such as neonatal phonation or rhythmogenesis in different physiological conditions.

SUBMITTER: da Silva CA

PROVIDER: S-EPMC10528911 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Role of NaV1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.

da Silva Carlos A CA Grover Cameron J CJ Picardo Maria Cristina D MCD Del Negro Christopher A CA

Cell reports 20230816 8

Inspiration is the inexorable active phase of breathing. The brainstem pre-Bötzinger complex (preBötC) gives rise to inspiratory neural rhythm, but its underlying cellular and ionic bases remain unclear. The long-standing "pacemaker hypothesis" posits that the persistent Na+ current (INaP) that gives rise to bursting-pacemaker properties in preBötC interneurons is essential for rhythmogenesis. We tested the pacemaker hypothesis by conditionally knocking out and knocking dow ...[more]

PMID: 37590134

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Project description:Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider Cyriopagopus schmidti, has been reported to be a potent antinociceptive compound due to its action on the genetically-validated NaV1.7 pain target. Using this peptide for antinociceptive applications in vivo suffers from one major drawback, namely its negative impact on the neuromuscular system. Although studied only recently, this effect appears to be due to an interaction between the peptide and the NaV1.6 channel subtype located at the presynaptic level. The aim of this work was to investigate how HwTx-IV could be modified in order to alter the original human (h) NaV1.7/NaV1.6 selectivity ratio of 23. Nineteen HwTx-IV analogues were chemically synthesized and tested for their blocking effects on the Na+ currents flowing through these two channel subtypes stably expressed in cell lines. Dose-response curves for these analogues were generated, thanks to the use of an automated patch-clamp system. Several key amino acid positions were targeted owing to the information provided by earlier structure-activity relationship (SAR) studies. Among the analogues tested, the potency of HwTx-IV E4K was significantly improved for hNaV1.6, leading to a decreased hNaV1.7/hNaV1.6 selectivity ratio (close to 1). Similar decreased selectivity ratios, but with increased potency for both subtypes, were observed for HwTx-IV analogues that combine a substitution at position 4 with a modification of amino acid 1 or 26 (HwTx-IV E1G/E4G and HwTx-IV E4K/R26Q). In contrast, increased selectivity ratios (>46) were obtained if the E4K mutation was combined to an additional double substitution (R 26A/Y33W) or simply by further substituting the C-terminal amidation of the peptide by a carboxylated motif, linked to a marked loss of potency on hNaV1.6 in this latter case. These results demonstrate that it is possible to significantly modulate the selectivity ratio for these two channel subtypes in order to improve the potency of a given analogue for hNaV1.6 and/or hNaV1.7 subtypes. In addition, selective analogues for hNaV1.7, possessing better safety profiles, were produced to limit neuromuscular impairments.

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Role of Na_V1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.

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Role of Na<sub>V</sub>1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.

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Role of NaV1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.

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Role of Na&lt;sub&gt;V&lt;/sub&gt;1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.

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OmicsDI is part of the ELIXIR infrastructure

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Role of Na_V1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.

Role of Na<sub>V</sub>1.6-mediated persistent sodium current and bursting-pacemaker properties in breathing rhythm generation.