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 TNF alpha, which enhances agonist-induced intracellular Ca2+ ([Ca2+](i)) responses, has been previously shown to increases CD38 expression. In the present study, we tested the hypothesis that the effects of TNF alpha on CD38 expression vs. changes in [Ca2+](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 [Ca2+](i) responses to sarcoplasmic reticulum depletion [i. e., store-operated Ca2+ entry (SOCE)] were evaluated in the presence vs. absence of TNF alpha. Results confirmed that TNF alpha 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 [Ca2+](i) responses. TNF alpha-induced enhancement of [Ca2+](i) response to agonist was blunted by CD38 suppression, but enhanced by CD38 overexpression. Finally, TNF alpha-induced increase in SOCE was blunted by CD38 siRNA and potentiated by CD38 overexpression. Overall, these results indicate a critical role for CD38 in TNF alpha-induced enhancement of [Ca2+](i) in human ASM cells, and potentially to TNF alpha augmentation of airway responsiveness.