The Braking K V 1/D-type Potassium Channels Regulate the Excitability of Bronchopulmonary Vagal Afferent Nerves.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology(2022)
Abstract
The proper function of airway vagal afferent nerves is essential for the dynamic regulation of breathing and initiation of adequate airway defensive reflexes. A better understanding of the mechanisms controlling their activation bears physiological and pathological significance. The voltage-gated potassium (K ) channels exert powerful controls on the neuronal excitability. Yet their expression and functions in the bronchopulmonary vagal afferent neurons remain largely unexplored. In this study we characterized the expression profile and inhibitory function of α-dendrotoxin (α-DTX)-sensitive D-type K channels composed of members of K 1subfamily of α-subunits in mouse bronchopulmonary nodose neurons using a combination of single-neurons RT-PCR, patch clamp recording, ex-vivo extracellular recording and two-photon microscopic Ca imaging techniques. The results showed that the vast majority of retrogradely labeled lung-specific nodose neurons expressed Kcna1, 2 and 6 coding for the α-DTX-sensitive K 1.1, 1.2 and 1.6 α-subunits, respectively. The D-type K current (I ), defined as the α-DTX-sensitive K current, was recorded in 14/15 bronchopulmonary nodose neurons. It started to be activated at -65.7±4.3 mV with 50% channel activation at -24 ± 14 mV. I opened rapidly in response to depolarization (activation time constants <10 ms at voltage ≥-15 mV), and displayed no inactivation during 600 ms at subthreshold/ threshold voltages and little or slow inactivation at more positive potentials (≥-5 mV). Inhibition of I with 50 nM α-DTX depolarized mouse pulmonary nodose neurons, increased input resistance, lowered the minimal depolarizing current needed to evoke an action potential, and increased the number and frequency of action potential firing in response to depolarizing current injections. Application of a bolus of 100 nM α-DTX to the afferent terminals in the mouse lungs via trachea led to overt activation in 49% of capsaicin-sensitive nodose neurons and in 32% of capsaicin-insensitive nodose neurons as detected by two-photon microscope. Further study with extracellular recording revealed that the application of an α-DTX bolus evoked action potential discharges in 8/19 (42%) nodose C-fibers terminating in the mouse lungs with a peak firing frequency of 4.4 ± 3.9 Hz. These results indicate that both the soma and terminals of bronchopulmonary nodose afferent nerves express functional I characterized by low-threshold, fast activation, and lack of or slow inactivation. With these unique biophysical properties, I channels act as an activation brake on the airway vagal afferent nerves by stabilizing the resting membrane potential and by counterbalancing the subthreshold depolarizing forces. Down-regulation of I , as occurs in many inflammatory diseases, may result in a heightened excitability of airway vagal afferent nerves causing exaggerated dyspnea, excessive mucous secretion, bronchoconstriction and chronic unproductive coughs associated with airway inflammation.
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Key words
bronchopulmonary vagal afferent nerves,potassium
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