In airway smooth muscle (ASM) cells, sarcoplasmic reticulum (SR) Ca2+ release via ryanodine receptor channels during acetylcholine (Ach) stimulation is mediated by cyclic ADP-ribose (cADPR), a metabolite of beta-NAD+. The enzymes for the synthesis and degradation of cADPR through ADP-ribosyl cyclase and cADPR hydrolase respectively are associated with a single bifunctional protein, CD38. In ASM, RT-PCR and Western blot analyses reveal CD38 expression. In ASM, Ach causes CD38 activation, reflected as increased ADP-ribosyl cyclase activity and cADPR production. Pre-incubation of ASM with 8-Br-cADPR, a cADPR antagonist results in attenuated Ca2+ responses and contraction to agonists. Agonists elicit decreased Ca2+ responses in ASM cells transfected with anti-sense CD38 and cells from CD38 knockout mice. These studies demonstrate the role of CD38/cADPR signaling in ASM Ca2+ regulation. cADPR-mediated SR Ca2+ release in porcine ASM cells is agonist specific. 8-Br-cADPR inhibits Ach- and ET-1-, but not histamine-, induced Ca2+ release. CD38/cADPR signaling is coupled to M2 muscarinic receptors, suggesting receptor subtype specific activation. Heightened [Ca2+]i response to agonists is a feature of airway inflammatory diseases. The pathogenesis involves alterations in gene expression and activation of second messengers involved in Ca2+ regulation. Inflammatory cytokines, IL-1beta, TNF-alpha and IFN-gamma up regulate CD38 expression and ADP-ribosyl cyclase activity in human ASM cells, where the [Ca2+]i responses to BK, Ach, histamine and thrombin are augmented and 8-Br-cADPR attenuates this response. In anti-sense CD38 transfected cells exposed to TNF-alpha, the [Ca2+]i responses to BK are lower than in controls. These findings have provided new insights into the role of CD38-cADPR-SR Ca2+ release in ASM hyperresponsiveness. The goal of the proposed studies is to obtain evidence for CD38 activation by multiple contractile agonists and its role in altered [Ca2+]i regulation and contractility of ASM in inflammatory diseases such as asthma. The overall hypothesis of the proposed study is that contractile agonists activate CD38/cADPR signaling in ASM cells to elevate [Ca2+]i, and cytokines upregulate CD38 expression, cADPR mediated calcium mobilization and contraction contributing to airway hyperresponsiveness. Our findings will lead to the development of potential drugs that target this signaling pathway.
| Guedes, Alonso G P; Jude, Joseph A; Paulin, Jaime et al. (2015) Airway responsiveness in CD38-deficient mice in allergic airway disease: studies with bone marrow chimeras. Am J Physiol Lung Cell Mol Physiol 308:L485-93 |
| Dileepan, Mythili; Jude, Joseph A; Rao, Savita P et al. (2014) MicroRNA-708 regulates CD38 expression through signaling pathways JNK MAP kinase and PTEN/AKT in human airway smooth muscle cells. Respir Res 15:107 |
| Jude, Joseph A; Tirumurugaan, Krishnaswamy G; Kang, Bit Na et al. (2012) Regulation of CD38 expression in human airway smooth muscle cells: role of class I phosphatidylinositol 3 kinases. Am J Respir Cell Mol Biol 47:427-35 |
| Jude, Joseph A; Dileepan, Mythili; Subramanian, Subbaya et al. (2012) miR-140-3p regulation of TNF-?-induced CD38 expression in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 303:L460-8 |
| Jude, Joseph A; Panettieri Jr, Reynold A; Walseth, Timothy F et al. (2011) TNF-? regulation of CD38 expression in human airway smooth muscle: role of MAP kinases and NF-?B. Adv Exp Med Biol 691:449-59 |
| Jude, Joseph A; Solway, Julian; Panettieri Jr, Reynold A et al. (2010) Differential induction of CD38 expression by TNF-{alpha} in asthmatic airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol 299:L879-90 |
| Kang, Bit Na; Jude, Joseph A; Panettieri Jr, Reynold A et al. (2008) Glucocorticoid regulation of CD38 expression in human airway smooth muscle cells: role of dual specificity phosphatase 1. Am J Physiol Lung Cell Mol Physiol 295:L186-93 |
| Guedes, Alonso G P; Jude, Joseph A; Paulin, Jaime et al. (2008) Role of CD38 in TNF-alpha-induced airway hyperresponsiveness. Am J Physiol Lung Cell Mol Physiol 294:L290-9 |
| Tirumurugaan, Krishnaswamy G; Kang, Bit Na; Panettieri, Reynold A et al. (2008) Regulation of the cd38 promoter in human airway smooth muscle cells by TNF-alpha and dexamethasone. Respir Res 9:26 |
| Jude, Joseph A; Wylam, Mark E; Walseth, Timothy F et al. (2008) Calcium signaling in airway smooth muscle. Proc Am Thorac Soc 5:15-22 |
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