Modulation of tracheal smooth muscle responses in inducible T-cell kinase knockout mice.
It has been shown that the Tec family nonreceptor tyrosine kinase inducible T cell kinase (ITK) plays a role in the activation of naive T cells and in the differentiation of T helper (TH2)-type cells producing cytokines in a model of allergic inflammation, thereby possibly indirectly mediating hyperresponsivenes of airway smooth muscle tone. Using excised tracheae from wild type (WT) mice and those lacking ITK, we conducted a series of in vitro experiments in which isometric smooth muscle tones were assessed in response to several agonists to determine whether the absence of ITK would affect the responsiveness of tracheal smooth muscle cells. The resulting change in contractile responses was evaluated by measuring agonist cumulative concentration-response curves (CCRC). Our results indicate that the cholinergic agonist acetylcholine (ACh) and its analog carbachol (CCh) exhibited comparable CCRC profiles in contracting isolated tracheae from both WT and ITK-/- mice, with no alteration in their efficacies. However, the EC50 values for the two agonists were found to be significantly higher in ITK-/- tracheae than in those from WT mice, suggesting an alteration of the potencies of these cholinergic agonists in the trachea of ITK-/- mice. Moreover, we found that the depolarizing agent potassium chloride (KCl) had a significantly lower efficacy in contracting ITK-/- tracheae compared to those from WT mice. This difference in KCl efficacy was abolished in the presence of a calcium (Ca2+) voltage-dependent channel (VDC) agonist, Bay K8644, suggesting a modulation of the KCl induced permeability of VDC Ca2+ channels in the trachea of ITK-/- mice. Taken together, these results suggest that the presence of ITK may play a modulating role in the pharmacomechanical as well as in the electromechanical coupling of airway smooth muscle contraction.
Intercollege Graduate Program in Physiology, Pennsylvania State University, University Park, PA 16802, USA.
Tanna J
TJ
Ferrara
Avery
A
August
Abdellaziz
A
Ben-Jebria
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured; D018679:Cholinergic Agonists / Q000494:pharmacology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects*; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000502:physiology*; D014132:Trachea / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology
D002120:Calcium Channel Agonists; D018679:Cholinergic Agonists; D009467:Neuromuscular Depolarizing Agents; D011189:Potassium Chloride; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002217:Carbachol; D011505:Protein-Tyrosine Kinases; D000109:Acetylcholine