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<p>Direct evidence regarding ion channel-mediated initiation of baroreflex/visceral neurotransmission remains limited. Here, aortic-arch, vagus-nodose slice, and isolated neurons were employed with single-fiber/whole-cell patch-clamp recordings to record instantaneous discharge of the aortic depressor nerve, spontaneous/evoked membrane depolarizations under different pharmacological interventions. Strikingly, profiles of A-fiber’s instantaneous firing frequency (IFF), including pressure threshold, rate, and sensitivity, were significantly reduced by 10 µmol/L flufenamic acid (FAA) and further suppressed by 3 µmol/L GsMTx4. Conversely, 3 µmol/L Yoda1-enhanced IFF was reversed by GsMTx4 and partially inhibited by FAA, consistent with step depolarization-evoked action potentials (APs). In &lt; 10% of A-type neurons, spontaneous APs accompanied by major (Ma-STPs) and minor sub-threshold depolarizations (Mi-STPs) were abolished by nanomolar tetrodotoxin. FAA only blocked spontaneous APs, while GsMTx4 suppressed both APs and Ma-STPs. The equal number of APs and Ma-STPs before and after FAA suggests that spontaneous APs initiate from Ma-STPs. Further, single-cell transcriptomic analysis revealed significant <i>Piezo1</i> and <i>TRPM4</i> co-expression in neurons. Gene co-expression and clustering analysis support their cooperative role in the baroreflex and visceral afferent pathways, validated by gene expression data. These findings demonstrate that TTX-sensitive Na<sup>+</sup> (TTX-S), <i>Piezo1</i>, and <i>TRPM4</i> channels each possess important intrinsic functions and play unique roles in the initiation of baroreflex/visceral neurotransmission.</p>

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Sub-threshold depolarization differentially regulated by multiple ion channels plays a key role in initiation of baroreflex afferent neurotransmission evidenced from baroreceptor terminals to its cell bodies

  • 期刊论文

  • 发表日期：

    2025年12月1日

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  • Yinzhi Xu,
  • Zhaoyuan Xu,
  • Huixiao Fu,
  • Mao Yue,
  • Jiaqun Li,
  • Changpeng Cui,
  • Xuelian Li,
  • Xianghui Kong,
  • Baiyan Li

摘要

Direct evidence regarding ion channel-mediated initiation of baroreflex/visceral neurotransmission remains limited. Here, aortic-arch, vagus-nodose slice, and isolated neurons were employed with single-fiber/whole-cell patch-clamp recordings to record instantaneous discharge of the aortic depressor nerve, spontaneous/evoked membrane depolarizations under different pharmacological interventions. Strikingly, profiles of A-fiber’s instantaneous firing frequency (IFF), including pressure threshold, rate, and sensitivity, were significantly reduced by 10 µmol/L flufenamic acid (FAA) and further suppressed by 3 µmol/L GsMTx4. Conversely, 3 µmol/L Yoda1-enhanced IFF was reversed by GsMTx4 and partially inhibited by FAA, consistent with step depolarization-evoked action potentials (APs). In < 10% of A-type neurons, spontaneous APs accompanied by major (Ma-STPs) and minor sub-threshold depolarizations (Mi-STPs) were abolished by nanomolar tetrodotoxin. FAA only blocked spontaneous APs, while GsMTx4 suppressed both APs and Ma-STPs. The equal number of APs and Ma-STPs before and after FAA suggests that spontaneous APs initiate from Ma-STPs. Further, single-cell transcriptomic analysis revealed significant Piezo1 and TRPM4 co-expression in neurons. Gene co-expression and clustering analysis support their cooperative role in the baroreflex and visceral afferent pathways, validated by gene expression data. These findings demonstrate that TTX-sensitive Na+ (TTX-S), Piezo1, and TRPM4 channels each possess important intrinsic functions and play unique roles in the initiation of baroreflex/visceral neurotransmission.