The long term objective is to identify and characterize the various components of taste transduction pathways to understand how they function in the taste cell. Of particular importance are taste cell guanine nucleotide binding regulatory proteins (G proteins) and the seven transmembrane helix receptors that couple to them. G proteins regulate effector enzymes such as phosphodiesterase and phospholipase to effect taste cell changes in intracellular second messengers (e.g., cAMP, cGMP, IP3, Ca2+). Gustducin is a taste specific G protein closely related to the transducins (the photoreceptor G proteins). Recently, it has been shown that rod transducin is also expressed in taste cells. These findings suggest that taste transduction may have some similarities to phototransduction. The specific goals of the proposal are the following: 1) to characterize gustducin's role in taste transduction using biochemical methods; 2) to purify, physically characterize and molecularly clone a recently identified taste specific phosphodiesterase (PDE); 3) to characterize the gustducin-PDE interaction using peptides and mutated gustducin and transducin proteins; 4) to characterize gustducin's role in taste transduction using behavioral and electrophysiological analysis of transgenic mice. Preliminary data indicate significant differences between gustducin knock out and wild type mice in their behavioral and electrophysiological responses to both sweet and bitter compounds; 5) the murine gustducin promoter will be used to express gustducin and transducin as transgenes in the taste cells of gustducin knock out mice. If transducin rescues knock out mice, it will indicate that gustducin and transducin are interchangeable in taste transduction; 6) transgenic mice will be made that express mutant gustducin deficient in its interaction with PDE. These transgenic animals will be tested behaviorally and electrophysiologically to determine if mutant gustducin also leads to altered bitter and sweet responses. Diverse methods will be required to address these goals: biochemical, transgenic, behavioral and electrophysiological techniques will be used. the results of these studies will provide significant new insights into the molecular mechanisms underlying taste transduction. Gustatory and metabolic disorders such as malgeusia, dysgeusia and cachexia frequently occur in conjunction with several types of cancer. The knowledge gained from this proposal may further our understanding of the molecular bases of taste disorders and eventually lead to effective intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC003055-05
Application #
6175389
Study Section
Sensory Disorders and Language Study Section (CMS)
Program Officer
Davis, Barry
Project Start
1996-08-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2002-07-31
Support Year
5
Fiscal Year
2000
Total Cost
$241,259
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Physiology
Type
Schools of Medicine
DUNS #
114400633
City
New York
State
NY
Country
United States
Zip Code
10029
Lewandowski, Brian C; Sukumaran, Sunil K; Margolskee, Robert F et al. (2016) Amiloride-Insensitive Salt Taste Is Mediated by Two Populations of Type III Taste Cells with Distinct Transduction Mechanisms. J Neurosci 36:1942-53
Sukumaran, Sunil K; Yee, Karen K; Iwata, Shusuke et al. (2016) Taste cell-expressed ?-glucosidase enzymes contribute to gustatory responses to disaccharides. Proc Natl Acad Sci U S A 113:6035-40
Howitt, Michael R; Lavoie, Sydney; Michaud, Monia et al. (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science 351:1329-33
Takai, Shingo; Yasumatsu, Keiko; Inoue, Mayuko et al. (2015) Glucagon-like peptide-1 is specifically involved in sweet taste transmission. FASEB J 29:2268-80
Lee, Robert J; Kofonow, Jennifer M; Rosen, Philip L et al. (2014) Bitter and sweet taste receptors regulate human upper respiratory innate immunity. J Clin Invest 124:1393-405
Kokrashvili, Zaza; Yee, Karen K; Ilegems, Erwin et al. (2014) Endocrine taste cells. Br J Nutr 111 Suppl 1:S23-9
Mokadem, Mohamad; Zechner, Juliet F; Margolskee, Robert F et al. (2014) Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency. Mol Metab 3:191-201
Ren, Wenwen; Lewandowski, Brian C; Watson, Jaime et al. (2014) Single Lgr5- or Lgr6-expressing taste stem/progenitor cells generate taste bud cells ex vivo. Proc Natl Acad Sci U S A 111:16401-6
Parker, M Rockwell; Feng, Dianna; Chamuris, Brianna et al. (2014) Expression and nuclear translocation of glucocorticoid receptors in type 2 taste receptor cells. Neurosci Lett 571:72-7
Lee, Robert J; Chen, Bei; Redding, Kevin M et al. (2014) Mouse nasal epithelial innate immune responses to Pseudomonas aeruginosa quorum-sensing molecules require taste signaling components. Innate Immun 20:606-17

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