Alveolar type II cells synthesize and store lung surfactant in lamellar bodies prior to secretion in the alveolar space. The synthesis, secretion, clearance, and degradation of surfactant components tightly regulate the alveolar pool of surfactant. In this context, the secretion of lung surfactant is probably most important, as it is the only means to acutely upregulate the alveolar pool of functionally active surfactant. The lamellar bodies are distinct organelles that are enclosed by a limiting membrane. The mechanism of membrane fusion between lamellar body and plasma membrane, an obligatory step during surfactant secretion, has remained poorly investigated. A role for lung synexin (annexin VII), a member of the 'annexins' family of proteins, in membrane fusion during surfactant secretion has been suggested. Synexin is present in type II cells, it binds to specific protein in lamellar body and plasma membrane, promotes in vitro fusion between these two fractions in a Ca2+-dependent manner, and increases surfactant secretion in permeabilized type II cells. Additionally, surfactant secretagogues increase synexin binding to type II cell membranes, and several inhibitors of synexin activity inhibit surfactant secretion. The overall goal of this project is to understand the regulation of membrane fusion during surfactant secretion through the study of structure-function analysis of synexin. Using deletion and substitution mutation constructs of rat synexin cDNA, recombinant protein and peptides will be expressed, purified, and characterized to determine the specific domains and amino acid residues that regulate self-association, membrane binding, membrane fusion, and secretion of lung surfactant. Phosphorylation-dependent regulation of synexin function will be studied using commercially available protein kinase enzymes that are implicated in surfactant secretion. Synexin contains several putative phosphorylation sites. Recombinant proteins with deletions and substitution mutations will be utilized for identification of specific domains and sites that are phosphorylated with these enzymes. The site specific phosphorylation in the regulation of synexin function will be verified with wild type and mutant synexin proteins using in vitro models of membrane binding, and surfactant secretion in permeabilized type II cells. The proposed studies will provide important information about the mechanism and regulation of synexin action in membrane fusion during surfactant secretion.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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Gail, Dorothy
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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Chander, Avinash; Gerelsaikhan, Tudevdagva; Vasa, Pavan K et al. (2013) Annexin A7 trafficking to alveolar type II cell surface: possible roles for protein insertion into membranes and lamellar body secretion. Biochim Biophys Acta 1833:1244-55
Gerelsaikhan, Tudevdagva; Vasa, Pavan Kumar; Chander, Avinash (2012) Annexin A7 and SNAP23 interactions in alveolar type II cells and in vitro: a role for Ca(2+) and PKC. Biochim Biophys Acta 1823:1796-806
Gerelsaikhan, Tudevdagva; Chen, Xiao-Liang; Chander, Avinash (2011) Secretagogues of lung surfactant increase annexin A7 localization with ABCA3 in alveolar type II cells. Biochim Biophys Acta 1813:2017-25
Shah, Shetal; Hudak 3rd, Joseph; Gad, Ashraf et al. (2010) Simulated transport alters surfactant homeostasis and causes dose-dependent changes in respiratory function in neonatal Sprague-Dawley rats. J Perinat Med 38:535-43
Cohen, J Craig; Killeen, Erin; Chander, Avinash et al. (2009) Small interfering peptide (siP) for in vivo examination of the developing lung interactonome. Dev Dyn 238:386-93
Gad, Ashraf; Callender, Delon L; Killeen, Erin et al. (2009) Transient in utero disruption of cystic fibrosis transmembrane conductance regulator causes phenotypic changes in alveolar type II cells in adult rats. BMC Cell Biol 10:24
Chander, Avinash; Chen, Xiao-Liang; Naidu, Devendra G (2007) A role for diacylglycerol in annexin A7-mediated fusion of lung lamellar bodies. Biochim Biophys Acta 1771:1308-18
Chander, Avinash; Naidu, Devendra G; Chen, Xiao-Liang (2006) A ten-residue domain (Y11-A20) in the NH2-terminus modulates membrane association of annexin A7. Biochim Biophys Acta 1761:775-84
Kirwin, Susan M; Bhandari, Vineet; Dimatteo, Darlise et al. (2006) Leptin enhances lung maturity in the fetal rat. Pediatr Res 60:200-4
Naidu, Devendra G; Raha, Abhijit; Chen, Xiao-Liang et al. (2005) Partial truncation of the NH2-terminus affects physical characteristics and membrane binding, aggregation, and fusion properties of annexin A7. Biochim Biophys Acta 1734:152-68

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