title: CD38/cyclic ADP-ribose-mediated Ca2+ signaling contributes to airway smooth muscle hyper-responsiveness.
abstract: We previously demonstrated that cyclic ADP-ribose (cADPR) elicits Ca2+ release in airway smooth muscle (ASM) cells through ryanodine receptor channels. CD38 is a cell surface protein that catalyzes the synthesis and degradation of cADPR. In inflammatory diseases such as asthma, augmented Ca2+ responses and Ca2+ sensitivity contribute to increased ASM contractility in response to agonists. In this study, we investigated the regulation of CD38 expression and the role of cADPR-mediated Ca2+ release in airway inflammation. Human ASM cells in culture between the second and fifth passages were exposed to tumor necrosis factor alpha (TNF-alpha), interleukin 1beta, or interferon gamma, or bovine serum albumin (controls). CD38 expression was measured by reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, and Western blot analysis, and ADP-ribosyl cyclase activity was assayed with nicotinamide guanine dinucleotide as the substrate. Ca2+ responses to acetylcholine, bradykinin, and thrombin were measured in fura-2AM-loaded cells by fluorescence microscopy. Cytokines caused significant augmentation of CD38 expression, ADP-ribosyl cyclase activity, and Ca2+ responses to the agonists, compared with the control. TNF-alpha effects were greater than those of the other two cytokines. The cADPR antagonist 8-bromo-cADPR attenuated the Ca2+ responses to the agonists in control and cytokine-treated cells, with the magnitude of inhibition correlating with the level of CD38. This study provides the first demonstration of a role for CD38-cADPR signaling in a model of inflammatory airway disease.
authors.affiliation: Department of Veterinary PathoBiology, University of Minnesota, St. Paul, Minnesota 55108, USA.
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Deshpande
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Walseth
authors.forename: Reynold A
authors.initials: RA
authors.lastname: Panettieri
authors.forename: Mathur S
authors.initials: MS
authors.lastname: Kannan
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D051997:ADP-ribosyl Cyclase 1; D000109:Acetylcholine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology*; D001920:Bradykinin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016535:Bronchial Hyperreactivity / Q000209:etiology; D020013:Calcium Signaling; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D006801:Humans; D008562:Membrane Glycoproteins; D008954:Models, Biological; D009119:Muscle Contraction; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis; D012143:Respiratory Physiological Phenomena; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D013917:Thrombin; D000109:Acetylcholine; D001920:Bradykinin