K(v)1/D-type potassium channels inhibit the excitability of bronchopulmonary vagal afferent nerves

The K(v)1/D-type potassium current (I-D) is an important determinant of neuronal excitability. This study explored whether and how I-D channels regulate the activation of bronchopulmonary vagal afferent nerves. The single-neuron RT-PCR assay revealed that nearly all mouse bronchopulmonary nodose neurons expressed the transcripts of alpha-dendrotoxin (alpha-DTX)-sensitive, I-D channel-forming K(v)1.1, K(v)1.2 and/or K(v)1.6 alpha-subunits, with the expression of K(v)1.6 being most prevalent. Patch-clamp recordings showed that I-D, defined as the alpha-DTX-sensitive K+ current, activated at voltages slightly more negative than the resting membrane potential in lung-specific nodose neurons and displayed little inactivation at subthreshold voltages. Inhibition of I-D channels by alpha-DTX depolarized the lung-specific nodose neurons and caused an increase in input resistance, decrease in rheobase, as well as increase in action potential number and firing frequency in response to suprathreshold current steps. Application of alpha-DTX to the lungs via trachea in the mouse ex vivo vagally innervated trachea-lungs preparation led to action potential discharges in nearly half of bronchopulmonary nodose afferent nerve fibres, including nodose C-fibres, as detected by the two-photon microscopic Ca2+ imaging technique and extracellular electrophysiological recordings. In conclusion, I-D channels act as a critical brake on the activation of bronchopulmonary vagal afferent nerves by stabilizing the membrane potential, counterbalancing the subthreshold depolarization and promoting the adaptation of action potential firings. Down-regulation of I-D channels, as occurs in various inflammatory diseases, may contribute to the enhanced C-fibre activity in airway diseases that are associated with excessive coughing, dyspnoea, and reflex bronchospasm and secretions.