Altered airway responsiveness in CD38-deficient mice.
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 < or = 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.
Deshpande
Deepak A
DA
Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, 1971 Commonwealth Avenue, Saint Paul, MN 55108, USA.
White
Thomas A
TA
Guedes
Alonso G P
AG
Milla
Carlos
C
Walseth
Timothy F
TF
Lund
Frances E
FE
Kannan
Mathur S
MS
D036541:ADP-ribosyl Cyclase / Q000235:genetics / Q000378:metabolism*; D051997:ADP-ribosyl Cyclase 1; D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D012137:Respiratory System / Q000378:metabolism*; D014665:Vasodilator Agents / Q000494:pharmacology
D015703:Antigens, CD; D019332:Endothelin-1; D008562:Membrane Glycoproteins; D014665:Vasodilator Agents; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D000109:Acetylcholine; D002118:Calcium