title: CD38 in the pathogenesis of allergic airway disease: Potential therapeutic targets.
abstract: CD38 is an ectoenzyme that catalyzes the conversion of β-nicotinamide adenine dinucleotide (β-NAD) to cyclic adenosine diphosphoribose (cADPR) and adenosine diphosphoribose (ADPR) and NADP to nicotinic acid adenine dinucleotide phosphate (NAADP) and adenosine diphosphoribose-2'-phosphate (ADPR-P). The metabolites of NAD and NADP have roles in calcium signaling in different cell types including airway smooth muscle (ASM) cells. In ASM cells, inflammatory cytokines augment CD38 expression and to a greater magnitude in cells from asthmatics, indicating a greater capacity for the generation of cADPR and ADPR in ASM from asthmatics. CD38 deficient mice develop attenuated airway responsiveness to inhaled methacholine following allergen sensitization and challenge compared to wild-type mice indicating its potential role in asthma. Regulation of CD38 expression in ASM cells is achieved by mitogen activated protein kinases, specific isoforms of PI3 kinases, the transcription factors NF-κB and AP-1, and post-transcriptionally by microRNAs. This review will focus on the role of CD38 in intracellular calcium regulation in ASM, contribution to airway inflammation and airway hyperresponsiveness in mouse models of allergic airway inflammation, the transcriptional and post-transcriptional mechanisms of regulation of expression, and outline approaches to inhibit its expression and activity.
authors.affiliation: Department of Medicine, Thomas Jefferson University, Philadelphia, USA.
authors.forename: Deepak A
authors.initials: DA
authors.lastname: Deshpande
authors.affiliation: Department of Veterinary Clinical Sciences, University of Minnesota at Twin Cities, USA.
authors.forename: Alonso G P
authors.initials: AGP
authors.lastname: Guedes
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, USA.
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
authors.affiliation: Department of Surgery, University of Minnesota at Twin Cities, USA.
authors.forename: Subbaya
authors.initials: S
authors.lastname: Subramanian
authors.affiliation: Department of Pharmacology, University of Minnesota at Twin Cities, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Walseth
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota at Twin Cities, USA. Electronic address: kanna001@umn.edu.
authors.forename: Mathur S
authors.initials: MS
authors.lastname: Kannan
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001249:Asthma / Q000503:physiopathology / Q000628:therapy; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000503:physiopathology* / Q000628:therapy; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009249:NADP / Q000378:metabolism; D012130:Respiratory Hypersensitivity / Q000503:physiopathology* / Q000628:therapy
chemical_list: D035683:MicroRNAs; D009243:NAD; D009249:NADP; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium
keywords: Airway smooth muscle; Asthma; CD38; Calcium regulation; MicroRNAs