I completed my undergraduate studies in the Department of Biology at the University of Virginia. I received my Ph.D. through the Whitney Laboratory and the Department of Neuroscience at the University of Florida under the mentorship of Barry W. Ache. Postdoctoral training was obtained in the laboratory of Randall Reed in the Howard Hughes Medical Institutes of Johns Hopkins University School of Medicine. I joined the faculty of the University of Maryland School of Medicine in the Department of Anatomy and Neurobiology in 2000. I am a member of the Programs in Neuroscience, Molecular Medicine, and Biochemistry, as well as the Training Program in Chemosensory Neuroscience and the Integrative Membrane Biology Training Program. Research in my laboratory is supported by grants from the National Institute on Deafness and Other Communication Disorders.
Mammals utilize several distinct populations of olfactory, vomeronasal and gustatory sensory cells to detect chemical cues that contain important information about the quality of food, the suitability of mates, and the presence of predators or competitors. Each of these cell populations expresses distinct receptors, channels and transduction cascades. For example, different populations of chemosensory neurons of the main olfactory epithelium and the vomeronasal organ express at least three distinct families of chemosensory receptors and utilize very different second messenger signaling systems upon receptor activation (Zufall and Munger, 2001). While many of these molecules have been identified, surprisingly little is known about how these various cell populations discriminate relevant chemical cues and why these tasks are distributed across so many cell types. If we are to elucidate the neural mechanisms used by animals to encode their chemical environment, it is essential that we understand how functional differences arise from the diversity of transduction mechanisms, and how, in turn, these differences instruct behavioral responses. The goal of our lab is to understand how the molecular diversity of G protein-coupled transduction mechanisms both contributes to chemosensory function and impacts ingestive and social behaviors.
The Receptor Basis of Taste Specificity
Perhaps the most striking difference between chemosensory cell populations is the receptors they express. We are taking advantage of the great diversity of G protein-coupled receptors (GPCRs) implicated in the recognition of chemical stimuli to ask how variations in receptor structure influence stimulus specificity. Receptors for sweet-, umami- (i.e., the taste of monosodium glutamate) and bitter-tasting compounds offer some unique advantages and are the main focus of our studies in this area. Using a combination of behavioral genetics, biophysics, protein biochemistry and molecular biology, we ask how variations in the structure of taste receptors influence the specificity of their interactions with sweet, bitter or amino acid taste stimuli. We then relate these findings to taste behaviors so that we may put our in vitro findings into an in vivo context.
The structure and function of sweet and umami taste receptors
T1R-type taste receptors interact with sweet and umami stimuli, including sugars, synthetic sweeteners, sweet-tasting proteins, and amino acids. We have developed a unique in vitro expression system that allows us to directly measure the interactions of these taste stimuli with T1R taste receptors (Nie et al, 2005; Nie et al, 2006). Mutating the receptors to reflect genetic variations in different strains or species, combined with behavioral testing in mice, has permitted us to begin to map those parts of the receptor that are critical for interactions with these stimuli. These studies may lead to the rational design of new sweeteners or food additives that could benefit individuals with diabetes or obesity.
The structural basis of sweetness
Why do some stimuli taste sweet? The most basic answer is that they interact, and activate, sweet taste receptors. However, the structural motifs that make a particular molecule a good ligand for the sweet receptor are not known. We are investigating this question by asking how structural changes in sweet proteins (a highly potent group of sweet stimuli) alters their ability to bind T1R receptors. We see that subtle changes in the structure of the sweet protein monellin that alter its perceived sweetnes also perturb the putative binding surface (Hobbs et al., 2007; Hobbs et al., in press). By correlating structural studies of monellin with biochemical assays of its interactions with T1Rs, we hope to identify the most critical determinants of sweet ligands.
The genetics of bitter taste
Inbred mouse strains provide a powerful tool to dissect out the genetic basis of complex behaviors, such as taste. These mice, which are genetically identical within each strain, often exhibit pronounced differences in their taste sensitivities to individual bitter compounds (Nelson et al., 2003, Boughter et al., 2005). By mapping the genes that are most important for these behavioral differences (much in the way that many disease genes have been identified in humans), we can begin to understand which receptors, and other molecules, are most important for these behaviors. In these studies we have focused on genes that contribute to bitter taste sensitivity, and have found that taste sensitivity to quinine is principally dependent on one or more T2R taste receptor genes (Nelson et al., 2005). We are now working to identify the individual receptors that underlie taste sensitivity to quinine and related compounds.
Taste, Eating Behaviors and Obesity
The sense of taste affects our food choices and eating habits and may have a significant impact on obesity, diabetes and related disorders. For example, children that have a particular variant of one bitter taste receptor are less likely to eat certain vegetables. In collaboration with faculty in the Department of Medicine, Division of Endocrinology, we are asking whether variations in human taste receptor genes (i.e., polymorphisms) are associated with obesity- and diabetes-related traits. We can then combine these genetic studies with in vitro characterizations of taste receptor function to better understand the relationships between taste function and disease.
The Molecular Basis of Olfactory Transduction
There are at least four spatially segregated subpopulations of sensory neurons within the nose, each projecting to different areas of the brain and each likely serving as somewhat distinct channels for different types of chemosensory information (Zufall and Munger, 2001). These discrete subpopulations of sensory cells appear to use unique biochemical cascades for the transduction of chemosensory molecules into electrical signals. We are using a combination of gene knockout, transgenic, molecular biological, biochemical and biophysical techniques in the mouse to decipher the transduction mechanisms of some of these specialized chemosensory systems, the ways in which the forebrain processes these signals, and the specific behaviors that they mediate.
Cyclic nucleotide-gated channels in olfactory transduction and adaptation
Cyclic nucleotide-gated channels (CNG channels) are critical for both visual and olfactory function. In olfactory sensory neurons, CNG channels mediate the initial odor-dependent depolarization of these cells. However, these channels are also the principal site of action for molecular mechanisms underlying short-term odor adaptation. Using gene-targeting strategies in mice, we found that one subunit of the olfactory channel, CNGA4 (Cockerham and Munger, 2005), is essential for both odor adaptation in olfactory sensory neurons (Munger et al., 2001) and for normal odor detection and discrimination in behaving animals (Kelliher et al., 2003). The roles of individual CNG channel subunits in olfactory function continues to be a major interest in the lab.
Specialized olfactory neurons
Subpopulations of sensory neurons in the main and accessory olfactory systems utilize distinct transduction mechanisms and exhibit unique projections to the forebrain (Zufall and Munger, 2001). Using gene-targeting, molecular biological and behavioral approaches, we are examining one of these subpopulations and its potential role in the detection of pheromones.
Lab Techniques and Equipment:
- Gene targeting in embryonic stem cells, generation of knockout/knockin and other transgenic mice
- Molecular biological, biophysical and biochemical techniques for the study of gene expression, protein function and protein interactions
- Tissue culture of mammalian cells
- Analysis of chemosensory-mediated behaviors
Current Lab Members
- Hyun Jin Choi, M.S.: Laboratory Technician
- Renee Cockerham, M.S.: Graduate Student, Program in Neuroscience
- Shawn Dotson, Ph.D.: Postdoctoral Fellow, Training Prog. Chemosensory Neurosci.
- Amanda Elson, M.S.: Graduate Student, Program in Neuroscience
- Lucy Newman, Ph.D.: Postdoctoral Fellow
- Daniel Shepherd, B.S.: Research Assistant
- Stephan Vigues, Ph.D.: Research Associate
Former Lab Members
- Yiling Nie, Ph.D. (Graduate Student in Anatomy and Neurobiology)--currently a postdoctoral associate at UCLA in the laboratory of H. Ronald Kaback
- Ted Nelson, Ph.D. (Graduate Student in Anatomy and Neurobiology)---currently a postdoc at the Monell Chemical Senses Center in the laboratory of Alexander Bachmanov
- Wendy Olson, Ph.D. (Postdoctoral Fellow, Training Program in Chemosensory Neuroscience) -- currently an instructor at the University of Maryland, Baltimore County
- Hobbs, J. H., Munger, S.D. and Conn, G.L. (2007) Monellin (MNEI) at 1.15 Ã… resolution. Acta Cryst. F63: 162-167
- Nie, Y., Hobbs, J.R., Vigues, S., Olson, W.J., Conn, G.L., and Munger, S.D. (2006) Expression and purification of functional ligand-binding domains of T1R3 taste receptors. Chem Senses. 31:505-513. OUP
- Nie, Y., Vigues, S., Hobbs, J.H., Conn, G.L. and Munger, S.D. (2005) Distinct contributions of T1R2 and T1R3 taste receptor subunits to the detection of sweet stimuli. Curr Biol. 15: 1948-1952. PubMed
- Boughter, Jr., J.D., Raghow, S., Nelson, T.M. and Munger, S.D. (2005) Inbred mouse strains C57BL/6J and DBA/2J vary in sensitivity to a subset of bitter stimuli. BMC Genetics. 6: 36. PubMed Central
- Nelson, T.M., Munger, S.D. and Boughter, Jr., J.D. (2005) Haplotypes at the Tas2r locus on distal chromosome 6 vary with quinine taste sensitivity in inbred mice. BMC Genetics. 6: 32. PubMed Central
- Cockerham, R.E. and Munger, S.D. (2005) CNGA4. AfCS-Nature Molecule Page.
- Nelson, T.M., Munger, S.D. and Boughter, Jr., J.D. (2003) PROP and PTC taste sensitivity vary independently in mice. Chem Senses. 28: 695-704. PubMed
- Kelliher, K.R., Ziesmann, J., Munger, S.D., Reed, R.R., and Zufall, F. Importance of the CNGA4 channel gene for odor discrimination and adaptation in behaving mice. Proc. Natl. Acad. Sci. USA. 100: 4299-4304. PubMed Central
- Munger, S.D., Lane, A.P., Zhong, H., Leinders-Zufall, T., Yau, K.-Y., Zufall, F. and Reed, R.R. (2001) Central role of the CNGA4 channel subunit in Ca2+-calmodulin-dependent odor adaptation. Science 294: 2172-2175. PubMed
- Zufall, F. and Munger, S.D. (2001) From odor/pheromone transduction to the organization of the sense of smell. Trends Neurosci. 24: 191-193. PubMed
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