The proposed studies will address very basic fundamental questions regarding signaling pathways involved in the regulation of intracellular Ca2+ ([Ca2+]i) in airway smooth muscle (ASM). The long-term goals of the proposed research are to understand the signaling pathways underlying ACh-induced [Ca2+]i oscillations in ASM cells and how these oscillations are coupled to force generation. In previous studies, we have shown that inositol 1,4,5- trisphosphate (IP3) and cyclic ADP ribose (cADPR;a metabolite of betaNAD) are produced in response to muscarinic stimulation and act as second messengers for SR Ca2+ release through IP3 and ryanodine receptor (RyR) channels, respectively. We further demonstrated that regulation of SR Ca2+ release is spatially and temporally dynamic, such that ACh induces repetitive localized [Ca2+]i oscillations that propagate through the cell. [Ca2+]i oscillations represent repetitive release of SR Ca2+ through RyR channels, while frequency and propagation velocity depend on agonist and cADPR concentrations. However, IP3 production and Ca2+ release through IP3 channels is also essential for initiation of [Ca2+]i oscillations. Propagating [Ca2+]j oscillations highlight the dynamic nature of SR Ca2+ release and its modulation by intracellular processes. Thus in ASM, [Ca2+]i oscillations are an important foundation underlying [Ca2+]j regulation and Ca2+ dependent processes such as force generation. The time constants of force generation and relaxation in ASM are slower than [Ca2+]i oscillations. Accordingly, localized force will summate depending on the frequency of [Ca2+]i oscillations and force coordination across the myocyte will depend on propagation velocity of [Ca2+]i oscillations. Our central hypothesis is that propagating [Ca2+]i oscillations in ASM cells reflect Ca2+ release through RyR channels, and that force generation by ASM depends on the frequency and propagation velocity of these [Ca2+]i oscillations.
The Specific Aims of the proposal are:
Aim 1 : To determine the distribution of IP3, and RyR channels in ASM cells;
Aim 2; To characterize SR Ca2+ release through IP3 and RyR channels in ASM;
Aim 3; To determine the time course of ACh-induced changes in IP3 and cADPR levels in ASM;
Aim 4; To determine the interactive roles of Ca2+ release through IP3R and RyR channels in ACh-induced [Ca2+]i oscillations in ASM cells.
Aim 5 : To determine the coupling between [Ca2+ ]i oscillations and force generation in ASM, In the proposed studies, we will examine the characteristics and inter-relationships of these SR Ca2+ release mechanisms vis-a-vis [Ca2+]i regulation and agonist-induced [Ca2+]i oscillations.
| Delmotte, Philippe; Sieck, Gary C (2015) Interaction between endoplasmic/sarcoplasmic reticulum stress (ER/SR stress), mitochondrial signaling and Ca(2+) regulation in airway smooth muscle (ASM). Can J Physiol Pharmacol 93:97-110 |
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| Sathish, Venkatachalem; Thompson, Michael A; Sinha, Sutapa et al. (2014) Inflammation, caveolae and CD38-mediated calcium regulation in human airway smooth muscle. Biochim Biophys Acta 1843:346-51 |
| Aravamudan, Bharathi; Kiel, Alexander; Freeman, Michelle et al. (2014) Cigarette smoke-induced mitochondrial fragmentation and dysfunction in human airway smooth muscle. Am J Physiol Lung Cell Mol Physiol 306:L840-54 |
| Jia, Li; Delmotte, Philippe; Aravamudan, Bharathi et al. (2013) Effects of the inflammatory cytokines TNF-? and IL-13 on stromal interaction molecule-1 aggregation in human airway smooth muscle intracellular Ca(2+) regulation. Am J Respir Cell Mol Biol 49:601-8 |
| Delmotte, Philippe; Yang, Binxia; Thompson, Michael A et al. (2012) Inflammation alters regional mitochondrial Ca²+ in human airway smooth muscle cells. Am J Physiol Cell Physiol 303:C244-56 |
| Wylam, Mark E; Xue, Ailing; Sieck, Gary C (2012) Mechanisms of intrinsic force in small human airways. Respir Physiol Neurobiol 181:99-108 |
| Aravamudan, Bharathi; VanOosten, Sarah K; Meuchel, Lucas W et al. (2012) Caveolin-1 knockout mice exhibit airway hyperreactivity. Am J Physiol Lung Cell Mol Physiol 303:L669-81 |
| Sathish, Venkatachalem; Abcejo, Amard J; Thompson, Michael A et al. (2012) Caveolin-1 regulation of store-operated Ca(2+) influx in human airway smooth muscle. Eur Respir J 40:470-8 |
| Sathish, Venkatachalem; Delmotte, Philippe F; Thompson, Michael A et al. (2011) Sodium-calcium exchange in intracellular calcium handling of human airway smooth muscle. PLoS One 6:e23662 |
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