title: Regulation of store-operated Ca2+ entry by CD38 in human airway smooth muscle.
abstract: The ectoenzyme CD38 catalyzes synthesis and degradation of cyclic ADP ribose in airway smooth muscle (ASM). The proinflammatory cytokine TNFalpha, which enhances agonist-induced intracellular Ca(2+) ([Ca(2+)](i)) responses, has been previously shown to increases CD38 expression. In the present study, we tested the hypothesis that the effects of TNFalpha on CD38 expression vs. changes in [Ca(2+)](i) regulation in ASM cells are linked. Using isolated human ASM cells, CD38 expression was either increased (transfection) or knocked down [small interfering RNA (siRNA)], and [Ca(2+)](i) responses to sarcoplasmic reticulum depletion [i.e., store-operated Ca(2+) entry (SOCE)] were evaluated in the presence vs. absence of TNFalpha. Results confirmed that TNFalpha significantly increased CD38 expression and ADP-ribosyl cyclase activity, an effect inhibited by CD38 siRNA, but unaltered by CD38 overexpression. CD38 suppression blunted, whereas overexpression enhanced, ACh-induced [Ca(2+)](i) responses. TNFalpha-induced enhancement of [Ca(2+)](i) response to agonist was blunted by CD38 suppression, but enhanced by CD38 overexpression. Finally, TNFalpha-induced increase in SOCE was blunted by CD38 siRNA and potentiated by CD38 overexpression. Overall, these results indicate a critical role for CD38 in TNFalpha-induced enhancement of [Ca(2+)](i) in human ASM cells, and potentially to TNFalpha augmentation of airway responsiveness.
authors.affiliation: Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. sieck.gary@mayo.edu
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
authors.forename: Thomas A
authors.initials: TA
authors.lastname: White
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thompson
authors.forename: Christina M
authors.initials: CM
authors.lastname: Pabelick
authors.forename: Mark E
authors.initials: ME
authors.lastname: Wylam
authors.forename: Y S
authors.initials: YS
authors.lastname: Prakash
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism; D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D001980:Bronchi / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D036563:Cyclic ADP-Ribose / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C493642:8-bromo-cyclic-ADP-ribose; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1