Potassium Channel Subtypes that Regulate Airway Vagal Sensory Nerve Excitability
Authors: Sun Hui , Patil Mayur , Ru Fei , Meeker Sonya , Undem Bradley J. 
Published: June 2021

Vagal sensory afferent nerves innervating the respiratory tracts play a defensive and homeostatic role in cardiopulmonary physiology. The majority of vagal afferent nerves in the airways are nociceptive in nature. Exaggerated activation of airway nociceptive nerve fibers by inflammatory mediators and other potentially noxious stimuli can lead to chronic cough, dyspnea, and aberrant reflex responses such as airway constriction and excessive mucus secretion. Most investigations on airway vagal nociceptive nerves have focused on the mediators and ion channels that underlie their activation while very little research attention has been given to the inhibitory K+ channels that operate at resting and/or subthreshold membrane potentials. These channels serve as brakes against excessive activation. In this study, we investigate the role of KCNQ/KV7/M‐channels, KCNA/KV1 channels and KCNK/two‐pore domain K+ (K2P) channels in regulating the intrinsic excitability of mouse nodose neurons and airway C‐fibers. Ultra‐low input RNA sequencing experiments showed that both lung‐specific and general population of isolated mouse nodose neurons express members of KV7, KV1, as well as TWIK, TASK and TREK subfamilies of K2P channels. Patch clamp recordings revealed an XE991‐sensitive KCNQ/KV7/M‐channel current (IM), α‐dendrotoxin (DTX)‐sensitive KV1‐mediated D‐current (ID) and an extracellular acidification‐inhibited TASK current in the majority of nodose neurons examined. IM activates around −65 mV with V1/2 for activation being at −38±3 mV. ID isolated with 10 nM α‐DTX has two components, and the low‐threshold component activates between −70 and −60 mV. At a holding potential of −60 mV, lowering the pH of the bath solution from 7.3 to 5.5 abolished the outward TASK current. The resting potential of mouse nodose neurons determined by perforated patch clamp technique averaged at −61±0.5 mV (n=65). Bath application of 10 μM M‐channel inhibitor XE991 or 30 nM ID channel blocker α‐DTX, or bath acidification led to a depolarization of 2 to 15 mV. Extracellular recordings of nodose neuron activities in the isolated and perfused vagus‐innervated mouse lung preparation revealed that the M‐channel opener retigabine applied locally to the lungs abolished the α,β‐meATP‐evoked action potential firing in pulmonary C‐fiber terminals. In the same kind of vagus‐lung preparations, application of 100 nM α‐DTX to the mouse lungs elicited action potential firing in about 20% of nodose fibers in the lungs as detected by two‐photon microscopy using mice expressing the Ca2+ indicator GCaMP6 under the Pirt promoter. In conclusion, our results indicate that KV7/M‐channels, KV1/ID channels and K2P/TASK channels contribute to maintaining the negative resting membrane potential in mouse nodose neurons and serve as a brake on their activation. Down regulation of these channels in visceral inflammatory diseases may contribute to sensory hyperexcitability. Alternatively, approaches enhancing the function of these K+ channels may be beneficial in the management of inflammatory diseases associated with vagal afferent hyperexcitability.(This study was conducted in conformance with the FASEB Statement of Principles for the use of Animals in Research and Education).Support or Funding InformationR01 HL122228; R01 HL137807‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.