Kegg Pathway: Taste transduction

J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2009 Nov 8;
Masala C, Solari P, Sollai G, Crnjar R, Liscia A

The study on transduction mechanisms underlying bitter stimuli is a particularly intriguing challenge for Taste researchers. The present study investigates, in the labellar chemosensilla of the blowfly Protophormia terraenovae, the transduction mechanism by which saccharin evokes the response of the "deterrent" cell, with particular attention to the contribution of K(+) and Ca(2+) current and the role of cyclic nucleotides, since second messengers modulate Ca(2+), Cl(-) and K(+) currents to different extents. As assessed by extracellular single-sensillum recordings, our results show that the addition of a Ca(2+) chelator such as EGTA or the Ca(2+) current blockers SK&F-96365, Mibefradil, Nifedipine and W-7 decrease the response of the "deterrent" cell to saccharin. A similar decreasing effect was also obtained following the addition of 4-aminopyridine, a K(+) current blocker. On the contrary, the membrane-permeable cyclic nucleotide 8-bromoguanosine 3',5'-cyclic monophosphate (8Br-cGMP) activates this cell and shows an additive effect when presented mixed with saccharin. Our results are consistent with the hypothesis that in the labellar chemosensilla of the blowfly both Ca(2+) and K(+) ions are involved in the transduction mechanism of the "deterrent" cell in response to saccharin. Our results also suggest a possible pathway common to saccharin and 8Br-cGMP.

Front Cell Neurosci. 2009; 3: 11
Fenech C, Patrikainen L, Kerr DS, Grall S, Liu Z, Laugerette F, Malnic B, Montmayeur JP

Taste receptors for sweet, bitter and umami tastants are G-protein-coupled receptors (GPCRs). While much effort has been devoted to understanding G-protein-receptor interactions and identifying the components of the signalling cascade downstream of these receptors, at the level of the G-protein the modulation of receptor signal transduction remains relatively unexplored. In this regard a Taste-specific regulator of G-protein signaling (RGS), RGS21, has recently been identified. To study whether guanine nucleotide exchange factors (GEFs) are involved in the transduction of the signal downstream of the Taste GPCRs we investigated the expression of Ric-8A and Ric-8B in mouse Taste cells and their interaction with G-protein subunits found in Taste buds. Mammalian Ric-8 proteins were initially identified as potent GEFs for a range of Galpha subunits and Ric-8B has recently been shown to amplify olfactory signal transduction. We find that both Ric-8A and Ric-8B are expressed in a large portion of Taste bud cells and that most of these cells contain IP3R-3 a marker for sweet, umami and bitter Taste receptor cells. Ric-8A interacts with Galpha-gustducin and Galphai2 through which it amplifies the signal transduction of hTas2R16, a receptor for bitter compounds. Overall, these findings are consistent with a role for Ric-8 in mammalian Taste signal transduction.

Cell Signal. 2010 Jan; 22(1): 150-7
Klasen K, Corey EA, Kuck F, Wetzel CH, Hatt H, Ache BW

Recent evidence has revived interest in the idea that phosphoinositides (PIs) may play a role in signal transduction in mammalian olfactory receptor neurons (ORNs). To provide direct evidence that odorants indeed activate PI signaling in ORNs, we used adenoviral vectors carrying two different fluorescently tagged probes, the pleckstrin homology (PH) domains of phospholipase C delta 1 (PLC delta 1) and the general receptor of phosphoinositides (GRP1), to monitor PI activity in the dendritic knobs of ORNs in vivo. Odorants mobilized PI(4,5)P(2)/IP(3) and PI(3,4,5)P(3), the substrates and products of PLC and PI3K. We then measured odorant activation of PLC and PI3K in olfactory ciliary-enriched membranes in vitro using a phospholipid overlay assay and ELISAs. Odorants activated both PLC and PI3K in the olfactory cilia within 2s of odorant stimulation. Odorant-dependent activation of PLC and PI3K in the olfactory epithelium could be blocked by enzyme-specific inhibitors. Odorants activated PLC and PI3K with partially overlapping specificity. These results provide direct evidence that odorants indeed activate PI signaling in mammalian ORNs in a manner that is consistent with the idea that PI signaling plays a role in olfactory transduction.

Eur Arch Otorhinolaryngol. 2009 Aug 29;
Gudziol V, Pietsch J, Witt M, Hummel T

Options for the treatment of hyposmia are limited; available therapies do not provide a long-lasting effect. A recent study suggests that an unspecific phosphodiesterase inhibitor (PDE-I) increases olfactory sensitivity due to interaction with the signal transduction in the olfactory epithelium. The aim of the present study was to investigate whether theophylline, an unspecific PDE-I, evokes changes in the electro-olfactogram (EOG) which would support the hypothesis of a drug-related impact on signal transduction. In addition, the uptake of topically administered theophylline in the olfactory epithelium should be investigated. EOG was obtained in 29 samples of supravital mouse olfactory epithelia. Olfactory stimulation (phenylethyl alcohol, PEA and hydrogen sulfide, H(2)S) was performed using an air-dilution olfactometer. Theophylline concentration in the olfactory epithelium of five samples was measured by means of high pressure liquid chromatography. Administration of theophylline resulted in a tendency towards smaller EOG amplitudes (p = 0.055), being reduced by 13 and 25% in response to stimulation with PEA or H(2)S, respectively. In comparison to the application of Ringer's solution, theophylline resulted in a significant (p = 0.031) decrease of the EOG amplitude. Latency was not significantly (p = 0.10) influenced by drug administration. The theophylline concentration in the olfactory epithelium ranged from 0.21 to 1.53 mug/mg. Theophylline seems to be taken up into the olfactory epithelium of supravital mice and to interact with the olfactory signal transduction.

Science. 2009 Aug 28; 325(5944): 1081-2
Kinnamon SC, Reynolds SD

Ann N Y Acad Sci. 2009 Jul; 1170: 682-7
Lans H, Dekkers MP, Hukema RK, Bialas NJ, Leroux MR, Jansen G

The lifespan of the nematode Caenorhabditis elegans is regulated by sensory signals detected by the amphid neurons. In these neurons, C. elegans expresses at least 14 Galpha subunits and a Ggamma subunit. We have identified seven sensory Galpha subunits that modulate lifespan. Genetic experiments suggest that multiple sensory signaling pathways exist that modulate lifespan and that some G proteins function in multiple pathways, most of which, but probably not all, involve insulin/IGF-1 like signaling. Interestingly, of the sensory G proteins involved in regulating lifespan, only one Galpha probably functions directly in the detection of sensory cues. The other G proteins seem to function in modulating the sensitivity of the sensory neurons. We hypothesize that in addition to the mere detection of sensory cues, regulation of the sensitivity of sensory neurons also plays a role in the regulation of lifespan.

Ann N Y Acad Sci. 2009 Jul; 1170: 596-603
Wang H, Zhou M, Brand J, Huang L

Taste disorders, including Taste distortion and Taste loss, negatively impact general health and quality of life. To understand the underlying molecular and cellular mechanisms, we set out to identify inflammation-related molecules in Taste tissue and to assess their role in the development of Taste dysfunctions. We found that 10 out of 12 mammalian Toll-like receptors (TLRs), type I and II interferon (IFN) receptors, and their downstream signaling components are present in Taste tissue. Some TLRs appear to be selectively or more abundantly expressed in Taste buds than in nongustatory lingual epithelium. Immunohistochemistry with antibodies against TLRs 1, 2, 3, 4, 6, and 7 confirmed the presence of these receptor proteins in Taste bud cells, of which TLRs 2, 3, and 4 are expressed in the gustducin-expressing type II Taste bud cells. Administration of TLR ligands, lipopolysaccharide, and double-stranded RNA polyinosinic:polycytidylic acid, which mimics bacterial or viral infection, activates the IFN signaling pathways, upregulates the expression of IFN-inducible genes, and downregulates the expression of c-fos in Taste buds. Finally, systemic administration of IFNs augments apoptosis of Taste bud cells in mice. Taken together, these data suggest that TLR and IFN pathways function collaboratively in recognizing pathogens and mediating inflammatory responses in Taste tissue. This process, however, may interfere with normal Taste transduction and Taste bud cell turnover and contributes to the development of Taste disorders.

Ann N Y Acad Sci. 2009 Jul; 1170: 383-91
de Araujo IE

Previous studies demonstrate that lesions to the rodent parabrachial nucleus (PBN) disrupt the formation of gustatory-postingestive associations, while preserving gustatory and viscerosensory functions. This suggests that the rodent PBN functions essentially as an integrative circuit, supporting the conditioning of tastants to postingestive factors. In the case of primates, however, anatomical studies have failed to demonstrate gustatory projections from medullary nuclei to PBN. It should therefore be inferred that the primate PBN lacks the associative functions assigned to its rodent counterpart. Moreover, the ability of rodent midbrain dopaminergic systems to respond to the activation of palatable tastants depends on the integrity of the gustatory PBN. However, recent studies demonstrate that caloric palatable compounds do not require Taste signaling to produce elevated brain dopamine levels. This raises the possibility that, in rodents, PBN neurons are important for the detection of postingestive effects of nutrients that occur independently of gustatory input. If confirmed, such function would assign non-associative roles to the rodent PBN, approximating its functional organization to its primate counterpart. We are currently testing this possibility by monitoring the behavioral responses to caloric glucose solutions in sweet-blind mice having sustained bilateral lesions to the PBN. Preliminary results indicate that the rodent PBN regulates nutrient intake even when no gustatory inputs are involved. This favors the assignment of non-gustatory, homeostatic functions to the rodent PBN during feeding, a concept that brings an additional perspective on the rodent versus primate functional discrepancy associated with the anatomy of this pontine nucleus.

Ann N Y Acad Sci. 2009 Jul; 1170: 98-101
Martin B, Dotson CD, Shin YK, Ji S, Drucker DJ, Maudsley S, Munger SD

Modulation of sensory function can help animals adjust to a changing external and internal environment. Even so, mechanisms for modulating Taste sensitivity are poorly understood. Using immunohistochemical, biochemical, and behavioral approaches, we found that the peptide hormone glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) are expressed in mammalian Taste buds. Furthermore, we found that GLP-1 signaling plays an important role in the modulation of Taste sensitivity: GLP-1R knockout mice exhibit a dramatic reduction in sweet Taste sensitivity as well as an enhanced sensitivity to umami-tasting stimuli. Together, these findings suggest a novel paracrine mechanism for the hormonal modulation of Taste function in mammals.

Ann N Y Acad Sci. 2009 Jul; 1170: 95-7
Chaudhari N, Kinnamon SC

Ann N Y Acad Sci. 2009 Jul; 1170: 91-4
Kokrashvili Z, Mosinger B, Margolskee RF

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that underlies the augmented insulin release from the pancreas in response to glucose in the gut lumen more than to intravenous injected glucose (the "incretin effect"). GLP-1, found in enteroendocrine L cells of the gut, regulates appetite and gut motility and is released from L cells in response to glucose. GLP-1-expressing duodenal L cells also express T1r Taste receptors, alpha-gustducin, and many other Taste transduction elements. Knockout mice lacking alpha-gustducin or T1r3 have deficiencies in secretion of GLP-1 and in the regulation of plasma levels of insulin and glucose. Gut-expressed Taste-signaling elements underlie multiple chemosensory functions of the gut including the incretin effect. Modulating hormone secretion from gut "Taste cells" may provide novel treatments for obesity, diabetes, and malabsorption.

Ann N Y Acad Sci. 2009 Jul; 1170: 77-81
Kondoh T, Tsurugizawa T, Torii K

Recent studies have demonstrated the existence of receptors for L-glutamate (GLU) and their transduction molecules in the gut mucosa as well as in the oral cavity. Among 20 amino acids, gastric vagal afferent fibers respond only to intragastric administration of GLU. Functional magnetic resonance imaging revealed activation of several forebrain regions in response to intragastric infusion of Taste solutions (D-glucose [sweet], monosodium L-glutamate [MSG; umami], and NaCl [salty] at 60 mM) in rats. Glucose activated the nucleus accumbens. MSG activated the medial preoptic area, dorsomedial nucleus of the hypothalamus, and habenular nucleus. Both glucose and MSG activated the amygdala. Some areas, such as the insular cortex, anterior cingulate cortex, hippocampus, and caudate-putamen were activated by all three substances. Glucose-induced brain activation developed slowly and persisted for a long time, whereas activation by MSG developed rapidly during infusion and reduced rapidly after cessation of infusion. NaCl induced only small and transient activation. Thus, both activated areas and temporal response patterns in the brain were distinct between sweet and umami substances delivered in the stomach. Postoral Taste substances may activate the brain via neural (vagal) and/or humoral pathways.

Ann N Y Acad Sci. 2009 Jul; 1170: 69-76
Horn CC

The alimentary canal includes the mouth, stomach, and intestines, and is connected to the brain by thousands of chemosensory neurons. In contrast to the understanding of the lingual Taste system, there is little insight into the chemosensory function of other regions of the alimentary canal. The presence of known Taste receptors in the gastrointestinal tract suggests a similarity to Taste mechanisms present in the oral cavity. Afferent fibers of the vagus play a prominent role in signaling the chemical contents of the gastrointestinal tract to the hindbrain and this information can be used to elicit defensive responses, such as vomiting or nutritional responses. A host of amino acids are likely detected by vagal afferent fibers, but the initial sensory transduction of these stimuli and functional significance remains a mystery. Several problems with recording the electrophysiological signals of vagal afferents are discussed, with particular reference to sampling the afferent signals from the duodenum and liver region.

Ann N Y Acad Sci. 2009 Jul; 1170: 55-9
Kinnamon SC, Vandenbeuch A

L-glutamate and 5'-ribonucleotides, such as GMP and IMP, elicit the "umami" Taste, also known as the fifth Taste. This review will highlight recent advancements in our understanding of umami Taste receptors and their downstream signaling effectors in Taste receptor cells. Several G protein-coupled receptors that bind umami stimuli have been identified in Taste buds, including the heterodimer T1R1/T1R3, truncated and brain forms of mGluR4 and mGluR1, brain mGluR2, and brain mGluR3. Further, ionotropic glutamate receptors are expressed in Taste cells and may play a role in glutamate transduction or signaling between Taste cells and/or nerve fibers. Knockout of T1R1 or T1R3 reduces, but does not eliminate, responses to umami stimuli, suggesting that multiple receptors contribute to umami Taste. The signaling effectors downstream of umami G protein-coupled receptors involve Gbetagamma activation of PLCbeta2 to elicit Ca(2+) release from intracellular stores and activation of a cation channel, TRPM5. In fungiform and palatal Taste buds, T1R1/T1R3 is co-expressed with Galpha gustducin and transducin, but the Galpha proteins involved in circumvallate Taste buds have not been identified. In most Taste fields, however, cAMP antagonizes responses to umami stimuli, suggesting that the Galpha subunit serves to modulate umami Taste sensitivity.

Ann N Y Acad Sci. 2009 Jul; 1170: 41-5
Delay ER, Eddy MC, Eschle BK

Psychophysical research with rats and mice has been instrumental in understanding umami Taste transduction and perception. Although early studies suggested that an NMDA-like receptor detected substances that elicit an umami Taste, studies using behavioral methods with both rats and mice indicate that the picture is much more complex. When the G protein-coupled receptor T1R1+T1R3 was discovered, it was believed to be the umami receptor and a more broadly tuned L-amino acid receptor. However, since then a number of behavioral studies, like molecular and physiological studies, report evidence that other receptors may contribute to umami Taste. For example, T1R3 knockout mice (KO) have only slightly elevated detection thresholds for monosodium glutamate (MSG) and L-alanine. In conditioned Taste aversion studies, T1R3 KO mice show bidirectional generalization of the aversion between MSG and L-alanine, suggesting that these substances have similar Tastes. However, these KO mice can discriminate between the Tastes of the two substances, indicating other receptors also respond to these amino acids. (RS)-alpha-cycloprophy-4-phosphonophenylglycine (CPPG), a potent mGluR4 antagonist, decreases an aversion to MSG in rats while increasing the strength of generalization of the aversion to L-arginine or L-serine. These behavioral studies suggest that glutamate can activate several putative receptors, most notably T1R1+T1R3 and Taste-mGluR4, and possibly NMDA-like receptors or Taste-mGluR1. These receptors generate similar but not identical sensations which, when combined, form a complex perception identified as umami. Further, these studies suggest that afferent signaling from T1R1+T1R3 and Taste-mGluR4 likely combine to generate the Taste sensations associated with other L-amino acids.

Ann N Y Acad Sci. 2009 Jul; 1170: 39-40
Ninomiya Y, Beauchamp GK

Ann N Y Acad Sci. 2009 Jul; 1170: 11-7
Liu HX, Grosse AM, Walton KD, Saims DA, Gumucio DL, Mistretta CM

Fungiform papillae are complex Taste organs that develop in a pattern on anterior tongue in rodent embryos. Several intrinsic secreted molecules are important for papilla development and patterning, including sonic hedgehog, bone morphogenetic proteins, Noggin, epidermal growth factor, and WNTs. Recent data about roles of WNTs in regulation of tongue and fungiform papilla development lead to new insights about the importance of tissue and timing contexts when studying the effects of morphogenetic proteins. WNT/beta-catenin signaling is required for formation of fungiform papillae, but not for determining tongue size and shape. In contrast, WNT5a apparently is important for tongue outgrowth, but not papilla development. Preliminary data from WNT5a mutant mice separate genetic programs for papilla number from those for tongue shape and size.

Am J Physiol Regul Integr Comp Physiol. 2009 Oct; 297(4): R1103-10
Guagliardo NA, West KN, McCluskey LP, Hill DL

Dietary sodium restriction coupled with axotomy of the rat chorda tympani nerve (CTX) results in selectively attenuated Taste responses to sodium salts in the contralateral, intact chorda tympani nerve. Converging evidence indicates that sodium deficiency also diminishes the activated macrophage response to injury on both the sectioned and contralateral, intact sides of the tongue. Because a sodium-restricted diet causes a robust increase in circulating aldosterone, we tested the hypothesis that changes in neurophysiological and immune responses contralateral to the CTX could be mimicked by aldosterone administration instead of the low-sodium diet. Taste responses in rats with CTX and supplemental aldosterone for 4-6 days were similar to rats with CTX and dietary sodium restriction. Responses to sodium salts were as much as 50% lower compared with sham-operated and vehicle-supplemented rats. The group-related functional differences were eliminated with lingual application of amiloride, suggesting that a major transduction pathway affected was through epithelial sodium channels. Consistent with the functional results, few macrophages were observed on either side of the tongue in rats with CTX and aldosterone. In contrast, macrophages were elevated on both sides of the tongue in rats with CTX and the vehicle. These results show that sodium deficiency or administration of aldosterone suppresses the immune response to neural injury, resulting in attenuation of peripheral gustatory function. They also show a potential key link among downstream consequences of sodium imbalance, Taste function, and immune activity.

Biochim Biophys Acta. 2009 Aug 4;
Assadi-Porter FM, Tonelli M, Maillet EL, Markley JL, Max M

The sweet receptor is a member of the G-protein coupled receptor family C that detects a wide variety of chemically and structurally diverse sweet-tasting molecules. We recently used saturation transfer difference spectroscopy (STD) to monitor the direct binding of a set of sweet agonists and antagonists to the human Taste receptor in membranes prepared from human embryonic kidney (HEK293) cells transfected with and expressing the sweet receptor [F.M. Assadi-Porter, M. Tonelli, E. Maillet, K. Hallenga, O. Benard, M. Max, J.L. Markley, J. Am. Chem. Soc. 130 (2008) 7212-7213]. Here we review this work and related studies, discuss the procedures involved, and expand on their potential for identifying specific binding interactions of ligands to the membrane spanning and extracellular regions of the full heterodimeric sweet Taste receptor. Whereas activity assays are unable to distinguish mutations that alter ligand-binding sites from those that alter signal transduction downstream of the binding site, STD NMR now allows us to make this distinction.

Am J Clin Nutr. 2009 Sep; 90(3): 733S-737S
Li X

The T1R family of Taste receptors mediates 2 Taste qualities: T1R2/T1R3 for sweet Taste and T1R1/T1R3 for umami Taste. Functional expression in heterologous system and gene knockout studies has shown their functions as Taste receptors. Structure-function relation studies on T1R2/T1R3 showed multiple ligand binding sites on both subunits. The umami Taste of l-glutamate can be drastically enhanced by 5' ribonucleotides, and the synergy is a hallmark of this Taste quality. On the basis of chimeric T1R receptors, site-directed mutagenesis, and molecular modeling data, we recently proposed a cooperative ligand binding model that involved the Venus flytrap domain of T1R1 in which l-glutamate binds close to the hinge region and 5' ribonucleotides bind to an adjacent site close to the opening of the flytrap to further stabilize the closed conformation. This novel mechanism may apply to other class C, G protein-coupled receptors.