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The Journal of Neuroscience, October 28, 2009, 29(43):13662-13671; doi:10.1523/JNEUROSCI.4354-08.2009

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Cellular/Molecular
Selective Expression of a Sodium Pump Isozyme by Cough Receptors and Evidence for Its Essential Role in Regulating Cough

Stuart B. Mazzone,¹ Sandra M. Reynolds,² Nanako Mori,² Marian Kollarik,² David G. Farmer,² Allen C. Myers,² and Brendan J. Canning²

¹School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland 4072, Australia, and ²The Johns Hopkins Asthma and Allergy Center, Baltimore, Maryland 21224

Correspondence should be addressed to Brendan J. Canning, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. Email: bjc{at}jhu.edu

We have identified a distinct subtype of airway vagal afferent nerve that plays an essential role in regulating the cough reflex. These afferents are exquisitely sensitive to punctate mechanical stimuli, acid, and decreases in extracellular chloride concentrations, but are insensitive to capsaicin, bradykinin, histamine, adenosine, serotonin, or changes in airway intraluminal pressures. In this study we used intravital imaging, retrograde neuronal tracing, and electrophysiological analyses to characterize the structural basis for their peculiar mechanical sensitivity and to further characterize the regulation of their excitability. In completing these experiments, we uncovered evidence for an essential role of an isozyme of Na⁺-K⁺ ATPase in regulating cough. These vagal sensory neurons arise bilaterally from the nodose ganglia and are selectively and brilliantly stained intravitally with the styryl dye FM2-10. Cough receptor terminations are confined and adherent to the extracellular matrix separating the airway epithelium and smooth muscle layers, a site of extensive remodeling in asthma and chronic obstructive pulmonary disease. The cough receptor terminals uniquely express the ₃ subunit of Na⁺-K⁺ ATPase. Intravital staining of cough receptors by FM2-10, cough receptor excitability in vitro, and coughing in vivo are potently and selectively inhibited by the sodium pump inhibitor ouabain. These data provide the first detailed morphological description of the peripheral terminals of the sensory nerves regulating cough and identify a selective molecular target for their modulation.

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Received Sept. 10, 2008; revised Aug. 22, 2009; accepted Aug. 26, 2009.

Correspondence should be addressed to Brendan J. Canning, The Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224. Email: bjc{at}jhu.edu

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