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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Noel, Patricia
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Rochester
United States
Zip Code
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
Sassoon, Catherine S H; Zhu, Ercheng; Fang, Liwei et al. (2014) Positive end-expiratory airway pressure does not aggravate ventilator-induced diaphragmatic dysfunction in rabbits. Crit Care 18:494
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
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
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; 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

Showing the most recent 10 out of 22 publications