title: Uridine adenosine tetraphosphate induces contraction of airway smooth muscle.
abstract: Contraction of airway smooth muscle (ASM) plays an important role in the regulation of air flow and is potentially involved in the pathophysiology of certain respiratory diseases. Extracellular nucleotides regulate ASM contraction via purinergic receptors, but the signaling mechanisms involved are not fully understood. Uridine adenosine tetraphosphate (Up(4)A) contains both pyrimidine and purine moieties, which are known to potentially activate P2X and P2Y receptors. Both P2X and P2Y receptors have been identified in the lung, including airway epithelial cells and ASM. We report here a study of purinergic signaling in the respiratory system, with a focus on the effect of Up(4)A on ASM contraction. Up(4)A induced contraction of rat isolated trachea and extrapulmonary bronchi as well as human intrapulmonary bronchioles. Up(4)A-induced contraction was blocked by di-inosine pentaphosphate, a P2X antagonist, but not by suramin, a nonselective P2 antagonist. Up(4)A-induced contraction was also attenuated by α,β-methylene-ATP-mediated P2X receptor desensitization. Several P2X receptors were detected at the mRNA level: P2X1, P2X4, P2X6, and P2X7, and to a lesser extent P2X3. Furthermore, the Up(4)A response was inhibited by removal of extracellular Ca(2+) and by the presence of the L-type Ca(2+) channel blocker, nifedipine, or the Rho-associated kinase inhibitor, H1152. We conclude that Up(4)A stimulates ASM contraction, and the underlying signaling mechanism appears to involve P2X (most likely P2X1) receptors, extracellular Ca(2+) entry via L-type Ca(2+) channels, and Ca(2+) sensitization through the RhoA/Rho-associated kinase pathway. This study will add to our understanding of the pathophysiological roles of extracellular nucleotides in the lung.
authors.affiliation: Dept. of Physiology & Pharmacology, Faculty of Medicine, Univ. of Calgary, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1. ygui@ucalgary.ca
authors.forename: Yu
authors.initials: Y
authors.lastname: Gui
authors.forename: ZengYong
authors.initials: Z
authors.lastname: Wang
authors.forename: XiaoRui
authors.initials: X
authors.lastname: Sun
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Xi-Long
authors.initials: XL
authors.lastname: Zheng
mesh_terms: D000818:Animals; D001980:Bronchi / Q000187:drug effects* / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000378:metabolism; D009213:Myography; D009543:Nifedipine / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism; D058469:Receptors, Purinergic P2X / Q000235:genetics / Q000378:metabolism*; D058470:Receptors, Purinergic P2Y / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013498:Suramin / Q000494:pharmacology; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D015226:Dinucleoside Phosphates; D047428:Protein Kinase Inhibitors; D058920:Purinergic P2X Receptor Antagonists; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058470:Receptors, Purinergic P2Y; C529314:uridine adenosine tetraphosphate; D013498:Suramin; D054460:rho-Associated Kinases; D009543:Nifedipine; D002118:Calcium