Chemosensory receptors and the basis of specificity

Summary

Principal Investigator: STEVEN MUNGER
Abstract: Mammals use several chemosensory systems to detect and encode their chemical environment. How these systems discriminate relevant chemical cues is a major unresolved question. We hypothesize that differences in the stimulus selectivity of different populations of chemosensory cells largely reflects differences in the ligand selectivity and sensitivity of the chemosensory receptors (CRs) expressed therein. Difficulties in obtaining large amounts of receptor protein suitable for biochemical or structural analysis, as well as the small number of CRs for which ligands are known, has hampered efforts to characterize the basis of ligand specificity. One group of CRs, the T1R taste receptors, offers unique advantages that will permit the first systematic analysis of how CR structure/function relationships impact the ability of a chemosensory cell population to detect and discriminate physiologically relevant ligands. We will take advantage of the demonstrated sensitivity of T 1Rs for sweet-tasting ligands, and an extracellular N-terminal ligand-binding domain amenable to biochemical purification and structural characterization, to establish the role of different T1Rs in the detection of sweet tasting stimuli. Aim 1: The structure of the T1R ligand-binding pockets, in the presence and absence of ligands, will be solved by a combination of circular dichroism spectrophotometry and X-ray crystallography of T1R N-terminal domains. Aim 2: To determine the specific contributions of ligand binding to taste function, targeted mutations will be introduced in the ligand-binding pocket of T1R N-terminal domains both in vitro and by gene targeting in mice. Changes in ligand binding kinetics will be measured using isothermal titration calorimetry, while the effects of T1R deletion or mutation on taste function will be assayed by brief-access behavioral tasks where the sensitivity of targeted mice to sweet stimuli will be determined. Together, these studies will provide the first in-depth structural and quantitative analyses of the interactions between chemosensory receptors and their ligands, and will offer important new insights into how individual taste receptors contribute to the detection and discrimination of food cues critical for health and survival.
Funding Period: 2009-08-14 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Reduced sweetness of a monellin (MNEI) mutant results from increased protein flexibility and disruption of a distant poly-(L-proline) II helix
    Catherine M Templeton
    Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
    Chem Senses 36:425-34. 2011
  2. ncbi T1R and T2R receptors: the modulation of incretin hormones and potential targets for the treatment of type 2 diabetes mellitus
    Cedrick D Dotson
    University of Maryland School of Medicine, Department of Anatomy and Neurobiology, Baltimore, MD 21201, USA
    Curr Opin Investig Drugs 11:447-54. 2010
  3. pmc Variation in the gene TAS2R38 is associated with the eating behavior disinhibition in Old Order Amish women
    Cedrick D Dotson
    Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Appetite 54:93-9. 2010
  4. pmc Modulation of taste sensitivity by GLP-1 signaling in taste buds
    Bronwen Martin
    National Institute on Aging NIH, Baltimore, Maryland, USA
    Ann N Y Acad Sci 1170:98-101. 2009
  5. ncbi Olfactory receptors: G protein-coupled receptors and beyond
    Marc Spehr
    Department of Chemosensation, Institute for Biology II, RWTH Aachen University, Aachen, Germany
    J Neurochem 109:1570-83. 2009
  6. pmc Bitter taste receptors influence glucose homeostasis
    Cedrick D Dotson
    Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
    PLoS ONE 3:e3974. 2008
  7. ncbi The receptor basis of sweet taste in mammals
    S Vigues
    Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Results Probl Cell Differ 47:187-202. 2009
  8. pmc Modulation of taste sensitivity by GLP-1 signaling
    Yu Kyong Shin
    National Institute on Aging NIH, Baltimore, Maryland 21224, USA
    J Neurochem 106:455-63. 2008
  9. pmc Monellin (MNEI) at 1.15 A resolution
    J R Hobbs
    Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, Manchester M60 1QD, England
    Acta Crystallogr Sect F Struct Biol Cryst Commun 63:162-7. 2007
  10. ncbi Expression and purification of functional ligand-binding domains of T1R3 taste receptors
    Yiling Nie
    Department of Anatomy and Neurobiology, Graduate Programs in Life Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Chem Senses 31:505-13. 2006

Scientific Experts

  • Graeme L Conn
  • Theodore M Nelson
  • John D Boughter
  • Cedrick D Dotson
  • Steven D Munger
  • Yu Kyong Shin
  • Nanette I Steinle
  • Bronwen Martin
  • Stephan Vigues
  • Catherine M Templeton
  • Marc Spehr
  • S Vigues
  • Braxton D Mitchell
  • Daniel J Drucker
  • Stuart Maudsley
  • Jeanette R Hobbs
  • Josephine M Egan
  • S D Munger
  • J R Hobbs
  • Yiling Nie
  • Ewan W Blanch
  • Saeideh Ostovar Pour
  • Hillary L Shaw
  • C D Dotson
  • Sunggoan Ji
  • Lan Zhang
  • Wook Kim
  • Hyun Jin Choi
  • Amanda E T Elson
  • Sandra H Ott
  • Hong Xu
  • Erin Golden
  • Xiaodong Li
  • Mark P Mattson
  • Hyeung Jin Jang
  • Hillary Shaw
  • Wendy J Olson

Detail Information

Publications12

  1. pmc Reduced sweetness of a monellin (MNEI) mutant results from increased protein flexibility and disruption of a distant poly-(L-proline) II helix
    Catherine M Templeton
    Department of Biochemistry, Emory University School of Medicine, Atlanta, GA 30322, USA
    Chem Senses 36:425-34. 2011
    ....
  2. ncbi T1R and T2R receptors: the modulation of incretin hormones and potential targets for the treatment of type 2 diabetes mellitus
    Cedrick D Dotson
    University of Maryland School of Medicine, Department of Anatomy and Neurobiology, Baltimore, MD 21201, USA
    Curr Opin Investig Drugs 11:447-54. 2010
    ..This review focuses on the intriguing finding that taste receptors may be involved in modulating the incretin response, and considers T1Rs and T2Rs as potential targets for new hypoglycemic drugs...
  3. pmc Variation in the gene TAS2R38 is associated with the eating behavior disinhibition in Old Order Amish women
    Cedrick D Dotson
    Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Appetite 54:93-9. 2010
    ..Therefore, our results indicate that a polymorphism in TAS2R38 is associated with differences in ingestive behavior...
  4. pmc Modulation of taste sensitivity by GLP-1 signaling in taste buds
    Bronwen Martin
    National Institute on Aging NIH, Baltimore, Maryland, USA
    Ann N Y Acad Sci 1170:98-101. 2009
    ..Together, these findings suggest a novel paracrine mechanism for the hormonal modulation of taste function in mammals...
  5. ncbi Olfactory receptors: G protein-coupled receptors and beyond
    Marc Spehr
    Department of Chemosensation, Institute for Biology II, RWTH Aachen University, Aachen, Germany
    J Neurochem 109:1570-83. 2009
    ..However, is has become clear that the 'family' of olfactory receptors is highly diverse, with roles for enzymes and ligand-gated ion channels as well as GPCRs in the primary detection of olfactory stimuli...
  6. pmc Bitter taste receptors influence glucose homeostasis
    Cedrick D Dotson
    Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD, USA
    PLoS ONE 3:e3974. 2008
    ..Together, these findings suggest that a functionally compromised TAS2R receptor negatively impacts glucose homeostasis, providing an important link between alimentary chemosensation and metabolic disease...
  7. ncbi The receptor basis of sweet taste in mammals
    S Vigues
    Department of Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Results Probl Cell Differ 47:187-202. 2009
    ..In this chapter, we discuss some of the mechanisms underlying the detection of sweeteners by mammals, with a particular focus on the function and role of the T1R2:T1R3 receptor in these processes...
  8. pmc Modulation of taste sensitivity by GLP-1 signaling
    Yu Kyong Shin
    National Institute on Aging NIH, Baltimore, Maryland 21224, USA
    J Neurochem 106:455-63. 2008
    ..A modest increase in citric acid taste sensitivity in these knockout mice suggests GLP-1 signaling may modulate sour taste, as well. Together, these findings suggest a novel paracrine mechanism for the regulation of taste function...
  9. pmc Monellin (MNEI) at 1.15 A resolution
    J R Hobbs
    Manchester Interdisciplinary Biocentre, Faculty of Life Sciences, University of Manchester, Manchester M60 1QD, England
    Acta Crystallogr Sect F Struct Biol Cryst Commun 63:162-7. 2007
    ..Four stably bound negative ions were also located, providing new insight into potential electrostatic interactions of MNEI with the largely negatively charged surface of the sweet taste receptor T1R2-T1R3...
  10. ncbi Expression and purification of functional ligand-binding domains of T1R3 taste receptors
    Yiling Nie
    Department of Anatomy and Neurobiology, Graduate Programs in Life Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA
    Chem Senses 31:505-13. 2006
    ..This methodology should not only facilitate the characterization of T1R ligand interactions but may also be useful for dissecting the function of other class C GPCRs such as the large family of orphan V2R vomeronasal receptors...
  11. pmc Inbred mouse strains C57BL/6J and DBA/2J vary in sensitivity to a subset of bitter stimuli
    John D Boughter
    Anatomy and Neurobiology, University of Tennessee Health Science Center, Memphis, TN 38163, USA
    BMC Genet 6:36. 2005
    ..Here, we used a taste-salient brief-access procedure to measure taste sensitivity to eight stimuli characterized as bitter or aversive in C57BL/6J (B6) and DBA/2J (D2) mice...
  12. pmc Haplotypes at the Tas2r locus on distal chromosome 6 vary with quinine taste sensitivity in inbred mice
    Theodore M Nelson
    Anatomy and Neurobiology, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA
    BMC Genet 6:32. 2005
    ..However, there is evidence for both receptor-dependent and -independent transduction mechanisms for a number of bitter stimuli, including quinine hydrochloride (QHCl) and denatonium benzoate (DB)...