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This Article Full Text Full Text (PDF) All Versions of this Article: 294/2/L378    most recent 00394.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sieck, G. C. Articles by Prakash, Y. S. Search for Related Content PubMed PubMed Citation Articles by Sieck, G. C. Articles by Prakash, Y. S.

Regulation of store-operated Ca²⁺ entry by CD38 in human airway smooth muscle

Departments of ¹Physiology and Biomedical Engineering, ²Anesthesiology, and ³Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota

Submitted 21 September 2007 ; accepted in final form 28 December 2007

The ectoenzyme CD38 catalyzes synthesis and degradation of cyclic ADP ribose in airway smooth muscle (ASM). The proinflammatory cytokine TNF, 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 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. Results confirmed that TNF 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-induced enhancement of [Ca²⁺]_i response to agonist was blunted by CD38 suppression, but enhanced by CD38 overexpression. Finally, TNF-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-induced enhancement of [Ca²⁺]_i in human ASM cells, and potentially to TNF augmentation of airway responsiveness.

bronchial smooth muscle; tumor necrosis factor-; sarcoplasmic reticulum; ADP ribosyl cyclase; cyclic ADP ribose; small interfering RNA