Regulation of airway contractility by plasminogen activators through N-methyl-D-aspartate receptor-1

Taher Nassar, Serge Yarovoi, Rami Abu Fanne, SA'Ed Akkawi, Mahmud Jammal, Timothy Craig Allen, Steven Idell, Douglas B. Cines, Abd Al Roof Higazi

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)703-711
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume43
Issue number6
DOIs
StatePublished - Dec 1 2010

Keywords

  • Lungs
  • Tissue plasminogen activator
  • Urokinase nmda receptor

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Regulation of airway contractility by plasminogen activators through N-methyl-D-aspartate receptor-1'. Together they form a unique fingerprint.

Cite this