Regulation of store-operated Ca2+ entry by CD38 in human airway smooth muscle.
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.
Sieck
Gary C
GC
Department of Physiology & Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. sieck.gary@mayo.edu
White
Thomas A
TA
Thompson
Michael A
MA
Pabelick
Christina M
CM
Wylam
Mark E
ME
Prakash
Y S
YS
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
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