Neurokinin-neurotrophin interactions in airway smooth muscle

Lucas W. Meuchel, Alecia Stewart, Dan F. Smelter, Amard J. Abcejo, Michael A. Thompson, Syed I.A. Zaidi, Richard J. Martin, Y. S. Prakash

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Neurally derived tachykinins such as substance P (SP) play a key role in modulating airway contractility (especially with inflammation). Separately, the neurotrophin brainderived neurotrophic factor (BDNF; potentially derived from nerves as well as airway smooth muscle; ASM) and its tropomyosin-related kinase receptor, TrkB, are involved in enhanced airway contractility. In this study, we hypothesized that neurokinins and neurotrophins are linked in enhancing intracellular Ca2+ concentration ([Ca2+]i) regulation in ASM. In rat ASM cells, 24 h exposure to 10 nM SP significantly increased BDNF and TrkB expression (P < 0.05). Furthermore, [Ca2+]i responses to 1 μ M ACh as well as BDNF (30 min) effects on [Ca2+]i regulation were enhanced by prior SP exposure, largely via increased Ca2+ influx (P < 0.05). The enhancing effect of SP on BDNF signaling was blunted by the neurokinin-2 receptor antagonist MEN-10376 (1 M, μP < 0.05) to a greater extent than the neurokinin-1 receptor antagonist RP-67580 (5 nM). Chelation of extracellular BDNF (chimeric TrkB-Fc; 1 μg/ml), as well as tyrosine kinase inhibition (100 nM K252a), substantially blunted SP effects (P < 0.05). Overnight (24 h) exposure of ASM cells to 50% oxygen increased BDNF and TrkB expression and potentiated both SPand BDNF-induced enhancement of [Ca2+]i (P < 0.05). These results suggest a novel interaction between SP and BDNF in regulating agonistinduced [Ca2+]i regulation in ASM. The autocrine mechanism we present here represents a new area in the development of bronchoconstrictive reflex response and airway hyperreactive disorders.

Original languageEnglish (US)
Pages (from-to)91-98
Number of pages8
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume301
Issue number1
DOIs
StatePublished - Jul 2011

Keywords

  • Brain-derived neurotrophic factor
  • Bronchial smooth muscle
  • Calcium
  • Hyperoxia
  • Oxygen
  • Substance p
  • Tropomyosin related kinase

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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  • Cite this

    Meuchel, L. W., Stewart, A., Smelter, D. F., Abcejo, A. J., Thompson, M. A., Zaidi, S. I. A., Martin, R. J., & Prakash, Y. S. (2011). Neurokinin-neurotrophin interactions in airway smooth muscle. American Journal of Physiology - Lung Cellular and Molecular Physiology, 301(1), 91-98. https://doi.org/10.1152/ajplung.00320.2010