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Altered Airway Responsiveness in CD38-Deficient Mice

Departments of Veterinary and Biomedical Sciences and Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul; Departments of Pediatrics and Pharmacology, College of Medicine, University of Minnesota, Minneapolis, Minnesota; and Trudeau Institute, Saranac Lake, New York

Correspondence and requests for reprints should be addressed to Mathur S. Kannan, BVSc, Ph.D., Professor of Pharmacology, Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, 1971 Commonwealth Avenue, Saint Paul, MN 55108. E-mail: kanna001{at}umn.edu

Cyclic ADP-ribose (cADPR) mobilizes calcium from intracellular stores and contributes to agonist-induced intracellular calcium elevation in airway smooth muscle (ASM). In this study we determined the functional role of CD38/cADPR signaling in the regulation of airway tone using CD38 deficient (cd38^–/–) mice. The responsiveness to different doses of methacholine, as determined by changes in lung resistance and dynamic compliance, was significantly (P 0.05) lower in cd38^–/– mice compared with wild-type controls. To determine the mechanism responsible for the reduced responsiveness, we measured the intracellular calcium responses to contractile agonists in ASM cells. In ASM cells isolated from cd38^–/– mice, the intracellular calcium responses to acetylcholine and endothelin-1 were significantly lower than in controls. Pretreatment of ASM cells with a cADPR antagonist resulted in attenuated intracellular calcium responses to endothelin-1 in cells isolated from wild-type mice, but not in those isolated from the cd38^–/– mice. Very low cADPR levels and no detectable ADP-ribosyl cyclase activity were observed in lung tissue from cd38^–/– mice, suggesting that CD38 is a critical source for cADPR synthesis. The results of the present study demonstrate that CD38/cADPR contributes to airway smooth muscle tone and responsiveness through its effects on agonist-induced elevation of intracellular calcium in ASM cells.

Key Words: CD38 • cADPR • airway • smooth muscle • responsiveness

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