Intracellular Ca2+ ([Ca2+]I) regulates a number of cellular processes in airway smooth muscle (ASM) in response to agonist stimulation. Recent studies from the principal investigator's laboratory indicate that agonists such as acetylcholine (Ach) and endothelin-1 induce [Ca2+]I oscillations in porcine ASM cells that reflect repetitive Ca2+ release through ryanodine receptor (RyR) channels of the sarcoplasmic reticulum (SR). Studies in non-smooth muscle tissue have demonstrated that cyclic ADP ribose (cADPR), metabolite of b-NAD, is a mediator for RyR activation. Preliminary studies related to this proposal also indicate that 1) cADPR is produced in ASM cells following agonist stimulation, 2) cADPR induces SR Ca2+ release through RyR channels, and 3) cADPR and its antagonist modulate agonist-induced [Ca2+]I oscillations. Additional studies also indicate that [Ca2+]I oscillations are frequency modulated in response to increasing agonist concentration as well as by cADPR. Slower Ca2+ -dependent cellular processes such as force production effectively integrate the faster [Ca2+]I oscillations. The overall hypothesis of the proposed studies is that cADPR, by affecting SR Ca2+ release through Ry channels, mediates agonist-induced [Ca2+]I oscillations in porcine ASM cells. The long-term goal of the proposed studies is to understand the signal transduction pathways underlying agonist-induced SR [Ca2+]I release in ASM cells. The proposed studies will determine the [Ca2+]I response to Ach and endothelin-1 stimulation in single ASM cells, and identify the role of cADPR i [Ca2+]I) regulation in ASM cells.
| 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 |
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| 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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