2009 Abstracts - Association for Chemoreception Sciences

#P195 Poster session IV: Chemosensory transductionand perireceptor eventsInhibition of bitter taste receptorsJay Slack 1 , Anne Brockhoff 2 , Batram Claudia 2 , Susann Menzel 2 ,Caroline Sonnabend 2 , Maik Behrens 2 , Nicole Brune 1 , IoanaUngureanu 1 , Christopher Simons 1 , Wolfgang Meyerhof 21Givaudan Flavors Corp Cincinnati, OH, USA, 2 German Instituteof Human Nutrition Potsdam-Rehbruecke Potsdam-Rehbrueke,GermanyIn humans, bitter taste is mediated by ~25 G protein-coupledreceptors of the hTAS2R family. For most TAS2Rs, severalcognate agonists have been identified suggesting that the TAS2Rspossess broad ligand spectra. Specific TAS2R inhibitors wouldallow for pharmacological analysis of the bitter response in vivoand reduction of unwanted bitterness in food and medicine. Byscreening a chemical compound library in cell-based receptorassays we found that 4-(1,1,2-trimethyl cyclopentanoyl-) butanoicacid (GR-81-3727) concentration-dependently blocked activationof hTAS2R44 by the sulfonyl amides saccharin and acesulfame-K,as well as by several other agonists. GR-81-3727 also abolished,with distinct potencies, agonist-induced responses of cellsexpressing various other hTAS2Rs, including hTAS2R43, which ishighly similar to hTAS2R44 and is also activated by thesulfonamides. In human sensory trials, GR-81-3727 effectivelyreduced the bitterness associated with ace-K and saccharin,indicating that it has physiological efficacy as a bitter tasteinhibitor. In vitro analyses employing chimeric receptors betweenhTASR44 and hTAS2R46 revealed that GR-81-3727 caused rightwardshifts of concentration-response functions and likely acts asa competitive antagonist. Notably, we also discovered that GR-81-3727 acted as an agonist at one hTAS2R. In similarexperiments, we also identified additional TAS2R antagonists withproperties similar to those of GR-81-3727. Together, our datademonstrate that the property of GR-81-3727 to interact withmultiple bitter receptors is a feature it shares with numerousTAS2R agonists. Our results also suggest unexpectedly complexinteractions between chemicals released from food in the mouthduring a meal with the family of TAS2Rs to elicit the bitterresponse.#P196 Poster session IV: Chemosensory transductionand perireceptor eventsSolitary chemosensory cells (SCCs) in the pancreasMarco Tizzano 1,2 , Zaza Kokrashvili 4 , Bedrich Mosinger 4 ,Sukumar Vijayaraghavan 3,2 , Robert F Margolskee 4 ,Thomas E Finger 1,21Cell & Development Biology, Univ. of Colorado at DenverAurora, CO, USA, 2 Rocky Mountain Taste & Smell CenterAurora, CO, USA, 3 Physiology and Biophysics, Univ. of Coloradoat Denver Aurora, CO, USA, 4 Department of Neuroscience,Mount Sinai School of Medicine New York, NY, USASolitary chemoreceptor cells (SCCs) are specialized cells of thegastrointestinal and respiratory tracts which detect and respond toa variety of compounds, including nutrients and irritants. Forexample, SCCs of the gut detect glucose by transductionmechanisms similar to those used by taste cells of the tongue toregulate secretion of insulin and hormones that affect appetite(Margolskee et al, 2007; Jang et al, 2007). In contrast, airway SCCsrespond to irritants and certain bitter substances (Lin et al. 2008;Gulbransen et al 2008). These diverse SCCs express manymarkers typical of taste cells including the G-protein gustducin,PLC 2, TrpM5, IP3R3, and bitter (T2Rs) and sweet/umamireceptors (T1Rs). The major pancreatic excretory ducts contain alarge number of specialized epithelial cells, named brush cells,which express gustducin (Hofer D & Drenckhahn D, 1998). Thefunction of pancreatic SCCs is unknown. Here we report thatmany of the SCCs in the pancreatic excretory ducts also expressGFP driven by the promoter for choline acetyltransferase (ChAT)or by the promoter for TrpM5. Further, TrpM5GFP+ SCCs aredetected in gall bladder, common bile duct and papilla of Vaterwhich sits at the exit of the pancreatic duct into the intestine.Many of the GFP+ SCCs also express gustducin and are sparselyinnervated by peptidergic (CGRP) sensory fibers. These findingssuggest that SCCs may release acetylcholine upon stimulation,thereby affecting the sensory afferents and/or surroundingtissues. Thus, chemosensory control of pancreatic secretion mightoccur via two independent mechanisms: hormonal (from the gut)and neural/paracrine from local SCCs. The SCCs associated withthe pancreatic ducts and papilla of Vater may providechemoreceptive feedback to regulate pancreatic secretions.#P197 Poster session IV: Chemosensory transductionand perireceptor eventsThe prenyl binding protein PrBP/d impedes trafficking ofG olf in olfactory sensory neurons (OSNs)Mavis A. Irwin 1 , Houbin Zhang 2 , Michelle Stamm 1 , WolfgangBaehr 2 , Mary Lucero 11University of Utah, Department of Physiology, NeuroscienceProgram Salt Lake City, UT, USA, 2 University of Utah,Department of Ophthalmology Salt Lake City, UT, USAThe ubiquitous prenyl binding protein, termed PrBP/d, isimportant in processing and targeting of prenylated proteins.We recently deleted the murine Pde6d gene (encoding PrBP/d),and observed that transport of GRK1 and PDE6 from theendoplasmic reticulum to the cilium of photoreceptors wasdisrupted and led to severe alterations in photoreceptorphysiology 1 . We used Pde6d -/- mice to identify the role of PrBP/din olfactory sensory neurons (OSNs). We found a dramaticdecrease in immunoreactivity for G olf in the cilia of Pde6d -/-OSNs but normal localization of ACIII. Initial behavioral testsshowed that most Pde6d -/- mice were capable of discriminatingbetween R and S carvone however investigation time wasreduced. Despite modest behavioral changes, electrical responsesto odorants were significantly reduced in Pde6d -/- mice. Peakamplitudes of electro-olfactograms (EOGs) of the odorantresponses to 2-heptanone, n-amyl acetate, and (-)-menthone inPde6d -/- mice (ages 16, 20, 23, and 28 months) were only 23± 10%of EOG responses in approximately age-matched control mice(4 knock out and 4 wild type; Student’s t-test p