title: Neurokinin-neurotrophin interactions in airway smooth muscle.
abstract: Neurally derived tachykinins such as substance P (SP) play a key role in modulating airway contractility (especially with inflammation). Separately, the neurotrophin brain-derived 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 Ca(2+) concentration ([Ca(2+)](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, [Ca(2+)](i) responses to 1 μM ACh as well as BDNF (30 min) effects on [Ca(2+)](i) regulation were enhanced by prior SP exposure, largely via increased Ca(2+) influx (P < 0.05). The enhancing effect of SP on BDNF signaling was blunted by the neurokinin-2 receptor antagonist MEN-10376 (1 μM, P < 0.05) to a greater extent than the neurokinin-1 receptor antagonist RP-67580 (5 nM). Chelation of extracellular BDNF (chimeric TrkB-F(c); 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 SP- and BDNF-induced enhancement of [Ca(2+)](i) (P < 0.05). These results suggest a novel interaction between SP and BDNF in regulating agonist-induced [Ca(2+)](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.
authors.affiliation: Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.
authors.forename: Lucas W
authors.initials: LW
authors.lastname: Meuchel
authors.forename: Alecia
authors.initials: A
authors.lastname: Stewart
authors.forename: Dan F
authors.initials: DF
authors.lastname: Smelter
authors.forename: Amard J
authors.initials: AJ
authors.lastname: Abcejo
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Syed I A
authors.initials: SI
authors.lastname: Zaidi
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Martin
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D018496:Hyperoxia / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000378:metabolism; D018040:Receptors, Neurokinin-1 / Q000378:metabolism; D018041:Receptors, Neurokinin-2 / Q000378:metabolism; D012137:Respiratory System / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D013373:Substance P; D020813:Receptor, trkB; D000109:Acetylcholine; D002118:Calcium