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 language | English (US) |
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Pages (from-to) | 91-98 |
Number of pages | 8 |
Journal | American Journal of Physiology - Lung Cellular and Molecular Physiology |
Volume | 301 |
Issue number | 1 |
DOIs | |
State | Published - 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