عنوان
پدید آورنده
موضوع
رده
کتابخانه
محل استقرار
TL49679
انگلیسی
Nicotinamide is a TRPV Channel Agonist in Caenorhabditis elegans and Drosophila melanogaster
[Thesis]
Awani Awani
Hanna-Rose, Wendy
The Pennsylvania State University
2017
136
Committee members: Gu, Ying; Lai, Zhi-Chun; Ordway, Richard W.; Rolls, Melissa
Place of publication: United States, Ann Arbor; ISBN=978-0-355-32963-6
Ph.D.
Molecular, Cellular, and Integrative Biosciences
The Pennsylvania State University
2017
Our ability to sense the environment around us and within the body is critical for survival. TRP ion channels are one family of sensory proteins that are implicated in almost every sensory modality i.e., touch, taste, smell, vision, hearing etc. (Islam, 2011). As a result, their dysfunction is implicated in many disease processes making them attractive drug targets (Moran et al., 2011; Nilius and Owsianik, 2010). TRP channels display remarkable diversity during evolution, yet they share many structural and functional similarities among evolutionally diverse species. Model organisms like Caenorhabditis elegans and Drosophila melanogaster provide a tractable system for investigating the complexities of these molecular sensors in a simpler setting. Metabolic regulation of TRP channels is an emerging field (Kahn-kirby et al., 1991; Kumar et al., 2014; Riera et al., 2014). My work reveals role of a form of vitamin B3, Nicotinamide (NAM) in modulating sensory signaling, behaviors and in some cases eliciting cell death via a TRPV channel in C. elegans and D. melanogaster. My lab has established an excellent C. elegans metabolic mutant model pnc-1 (pyrazinamidase/nicotinamidase-1) to study how metabolism affects biological processes like development, aging and cell death. I began my research by investigating a cell death phenotype in the pnc-1 mutant. Loss of C. elegans nicotinamidase pnc-1 that is required for NAD salvage synthesis causes metabolic perturbation and increase in its substrate NAM levels (Vrablik et al., 2009). Four cells in the uterus (uterine-vulval 1 cells) of the animal die due to excess NAM in pnc-1 mutant. Here I report that NAM inflicts death on another set of cells found in the head (OLQ neurons) of the animal. I show that the death phenotype is limited to these two cell types because they both express a heteromeric TRPV ion channel made up of OCR-4 and OSM-9 subunits, coexpression of these is necessary for NAM induced cell death. Using electrophysiology in Xenopus oocytes, I determine that NAM is a direct agonist for OCR-4/OSM-9 TRPV ion channel. This is the first successful report of in vitro functional expression any C. elegans TRPV channel. C. elegans TRPV channels are not well characterized and I propose that NAM agonist provides a tool for the same. I further show that NAM agonist activity on TRPV channels is conserved in D. melanogaster. In Drosophila, Nanchung (Nan) and Inactive (Iav) are the OCR- 4 and OSM-9 orthologos respectively. Nan/Iav hetromer is also activated by NAM in electrophysiology in Xenopus oocytes. Calcium imaging in Drosophila larvae shows that NAM application induces a calcium spike and over stimulates the chordotonal neurons (the only cells that co-express Nan/Iav hetromer) and renders them inactive. I also show that behaviors mediated by the orthologous Drosophila channel are responsive to NAM. These results provide an intriguing link between metabolic regulation and TRPV channel activity thus opening avenues for future research.
Genetics
Biological sciences;C. elegans;Necrosis;Nicotinamide;OLQ cells;TRPV channels;uv1 cells
Kalinsky, Joseph Mordechai
Hanna-Rose, Wendy
Molecular, Cellular, and Integrative Biosciences
The Pennsylvania State University
1983947135; 10666421
مطالعه متن کتاب p
[Thesis]
276903
a
Y
