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Stimulus intensity-dependent recruitment of Na_V1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.

ABSTRACT: We investigated voltage-gated sodium channel (Na_V1) 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. Na_V1 inhibitors were selectively delivered to the tissue-containing nerve terminals. Graded esophageal distention was used for mechanical stimulation. The Na_V1.7 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 Na_V1.7, 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 Na_V1s. The group Na_V1.1, Na_V1.2, and Na_V1.3 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 Na_V1.7 and Na_V1.6, 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 Na_V1.7. However, the response evoked by higher (noxious) levels of esophageal distention has a progressively increasing Na_V1.7-independent component that involves multiple TTX-sensitive Na_V1s. The stimulus intensity-dependent recruitment of Na_V1s may offer novel opportunities for strategic targeting of Na_V1 subunits for inhibition of nociceptive signaling in visceral C-fibers.NEW & NOTEWORTHY We report that pharmacologically distinguishable voltage-gated sodium channels (Na_V1) 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 Na_V1.7; however, additional tetrodotoxin (TTX)-sensitive Na_V1s are recruited at higher intensity of distention. This is the first demonstration that Na_V1s underlying action potential initiation in visceral C-fibers depend on the intensity of the stimulus.

SUBMITTER: Ru F

PROVIDER: S-EPMC7654645 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The lungs and esophagus are innervated by sensory neurons with somata in the nodose, jugular, and dorsal root ganglion. These sensory ganglia are derived from embryonic placode (nodose) and neural crest tissues (jugular and dorsal root ganglia; DRG). We addressed the hypothesis that the neuron's embryonic origin (e.g., placode vs. neural crest) plays a greater role in determining particular aspects of its phenotype than the environment in which it innervates (e.g., lungs vs. esophagus). This hypothesis was tested using a combination of extracellular and patch-clamp electrophysiology and single-cell RT-PCR from guinea pig neurons. Nodose, but not jugular C-fibers innervating the lungs and esophagus, responded to alpha,beta-methylene ATP with action potential discharge that was sensitive to the P2X3 (P2X2/3) selective receptor antagonist A-317491. The somata of lung- and esophagus-specific sensory fibers were identified using retrograde tracing with a fluorescent dye. Esophageal- and lung-traced neurons from placodal tissue (nodose neurons) responded similarly to alpha,beta-methylene ATP (30 microM) with a large sustained inward current, whereas in neurons derived from neural crest tissue (jugular and DRG neurons), the same dose of alpha,beta-methylene ATP resulted in only a transient rapidly inactivating current or no detectable current. It has been shown previously that only activation of P2X2/3 heteromeric receptors produce sustained currents, whereas homomeric P2X3 receptor activation produces a rapidly inactivating current. Consistent with this, single-cell RT-PCR analysis revealed that the nodose ganglion neurons innervating the lungs and esophagus expressed mRNA for P2X2 and P2X3 subunits, whereas the vast majority of jugular and dorsal root ganglia innervating these tissues expressed only P2X3 mRNA with little to no P2X2 mRNA expression. We conclude that the responsiveness of C-fibers innervating the lungs and esophagus to ATP and other purinergic agonists is determined more by their embryonic origin than by the environment of the tissue they ultimately innervate.

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Stimulus intensity-dependent recruitment of Na_V1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.

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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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OmicsDI is part of the ELIXIR infrastructure

Tweets

Stimulus intensity-dependent recruitment of Na_V1 subunits in action potential initiation in nerve terminals of vagal C-fibers innervating the esophagus.