Regulation of airway contractility by plasminogen activators through N-methyl-D-aspartate receptor-1.
Reactive airway disease is mediated by smooth muscle contraction initiated through several agonist-dependent pathways. Activation of type 1 N-methyl-D-aspartate receptors (NMDA-R1s) by plasminogen activators (PAs) has been linked to control of vascular tone, but their effect on airway smooth muscle contractility has not previously been studied to our knowledge. We observed that NMDA-R1s are expressed by human airway smooth muscle cells and constitutively inhibit the contraction of isolated rat tracheal rings in response to acetylcholine (Ach). Both tissue-type PA (tPA) and urokinase-type PA (uPA) bind to NMDA-R1 and reverse this effect, thereby enhancing Ach-induced tracheal contractility. Tracheal contractility initiated by Ach is reduced in rings isolated from tPA(-/-) and uPA(-/-) mice compared with their wild-type counterparts. The procontractile effect of uPA or tPA was mimicked and augmented by the nitric oxide synthase inhibitor, l-NAME. uPA and tPA further enhanced the contractility of rings denuded of epithelium, an effect that was inhibited by the NMDA-R antagonist, MK-801. Binding of PAs to NMDA-R1 and the subsequent activation of the receptor were inhibited by PA inhibitor type 1, by a PA inhibitor type 1-derived hexapeptide that recognizes the tPA and uPA docking domains, as well as by specific mutations within the docking site of tPA. These studies identify involvement of PAs and NMDA-R1 in airway contractility, and define new loci that could lead to the development of novel interventions for reactive airway disease.
Nassar
Taher
T
Department of Pathology and Laboratory Medicine, University of Pennsylvania, 513A Stellar-Chance, 422 Curie Boulevard, Philadelphia, PA 19104, USA.
Yarovoi
Serge
S
Fanne
Rami Abu
RA
Akkawi
Sa'ed
S
Jammal
Mahmud
M
Allen
Timothy Craig
TC
Idell
Steven
S
Cines
Douglas B
DB
Higazi
Abd Al-Roof
AA
D000818:Animals; D001665:Binding Sites; D055162:Biocatalysis / Q000187:drug effects; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D010959:Tissue Plasminogen Activator / Q000378:metabolism* / Q000494:pharmacology; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism* / Q000494:pharmacology
D017395:Plasminogen Activator Inhibitor 1; D016194:Receptors, N-Methyl-D-Aspartate; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D019331:NG-Nitroarginine Methyl Ester