Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.
Stimulus intensity-dependent recruitment of NaV1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.
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NaV1 亚基在支配食管的迷走神经 C 纤维神经末梢的动作电位启动中的刺激强度依赖性募集。
DOI：
10.1152/ajpgi.00122.2019
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Kollarik,Marian
中科院分区：
文献类型：
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作者：
Ru,Fei;Pavelkova,Nikoleta;Krajewski,JeffreyL;McDermott,JeffS;Undem,BradleyJ;Kollarik,Marian
我们研究了电压门控钠通道(NAV1)亚单位，它调节支配食道的迷走神经结状C纤维神经末梢的动作电位起始。用机械敏感神经末梢记录豚鼠食道结状C纤维的细胞外单纤维。NAV1抑制剂被选择性地输送到含有组织的神经末梢。机械刺激采用分级扩张食道。NAV1.7抑制剂PF-05089771几乎取消了对低水平食道扩张反应的动作电位启动，但仅部分抑制了对较高水平食道扩张的反应。PF-05089771反应的不敏感成分随着食道扩张的增加而逐渐增加(最高可达≈的50%)，并被河豚毒素所消除。除Nav1.7外，从食道逆行标记的结状C纤维[瞬时受体电位通道-香草亚家族成员1(TRPV1)阳性]神经元表达多个对TTX敏感的NaV1的mRNA。NAV1.1、NAV1.2和NAV1.3抑制剂ICA-121431组抑制但不取消对高水平食道扩张反应的PF-05089771不敏感部分。然而，ICA-121431与同样抑制NA1.7和NAV1.6的化合物801联合使用，几乎消除了对高水平食道扩张的反应。我们的数据表明，低水平(无害的)食道扩张所诱发的食道结状C纤维的动作电位起始点是由Nav1.7介导的。然而，更高水平(有害的)食道扩张引起的反应有一个逐步增加的Nav1.7独立成分，涉及多个TTX敏感的NaV1。依赖刺激强度的NaV1的募集可能为策略靶向NAV1亚单位抑制内脏C纤维伤害性信号提供新的机会。新与报道我们报道，在迷走神经结状C纤维的神经末梢，药理可区分的电压门控钠通道(NAV1)介导低(无害)和高(伤害)强度的食道扩张的动作电位起始。低强度的动作电位启动完全依赖于Nav1.7；然而，在较高的扩张强度时，会招募额外的河豚毒素(TTX)敏感的NaV1。这是第一次证明内脏C-纤维中NAV1的潜在动作电位的启动依赖于刺激的强度。
We investigated voltage-gated sodium channel (NaV1) subunits that regulate action potential initiation in the nerve terminals of vagal nodose C-fibers innervating the esophagus. Extracellular single fiber recordings were made from the nodose C-fibers, with mechanically sensitive nerve terminals in the isolated innervated guinea pig esophagus. NaV1 inhibitors were selectively delivered to the tissue-containing nerve terminals. Graded esophageal distention was used for mechanical stimulation. The NaV1.7 inhibitor PF-05089771 nearly abolished action potential initiation in response to low levels of esophageal distention but only partially inhibited the response to higher levels of esophageal distention. The PF-05089771-insensitive component of the response progressively increased (up to ≈50%) with increasing esophageal distention and was abolished by tetrodotoxin (TTX). In addition to NaV1.7, nodose C-fiber [transient receptor potential channel-vanilloid subfamily member 1 (TRPV1)-positive] neurons retrogradely labeled from the esophagus expressed mRNA for multiple TTX-sensitive NaV1s. The group NaV1.1, NaV1.2, and NaV1.3 inhibitor ICA-121431 inhibited but did not abolish the PF-05089771-insensitive component of the response to high level of esophageal distention. However, combination of ICA-121431 with compound 801, which also inhibits NaV1.7 and NaV1.6, nearly abolished the response to the high level of esophageal distention. Our data indicate that the action potential initiation in esophageal nodose C-fibers evoked by low (innocuous) levels of esophageal distention is mediated by NaV1.7. However, the response evoked by higher (noxious) levels of esophageal distention has a progressively increasing NaV1.7-independent component that involves multiple TTX-sensitive NaV1s. The stimulus intensity-dependent recruitment of NaV1s may offer novel opportunities for strategic targeting of NaV1 subunits for inhibition of nociceptive signaling in visceral C-fibers.NEW & NOTEWORTHYWe report that pharmacologically distinguishable voltage-gated sodium channels (NaV1) mediate action potential initiation at low (innocuous) versus high (noxious) intensity of esophageal distention in nerve terminals of vagal nodose C-fibers. Action potential initiation at low intensity is entirely dependent on NaV1.7; however, additional tetrodotoxin (TTX)-sensitive NaV1s are recruited at higher intensity of distention. This is the first demonstration that NaV1s underlying action potential initiation in visceral C-fibers depend on the intensity of the stimulus.