REPUBLICA DE COLOMBIA DEPARTAMENTO DEL META MUNICIPIO FUENTEDEORO MUNICIPIO DE FUENTEDEORO INVITACION PÚBLICA No. 045 de 2010 "EL SUMINISTRO DE LOS MEDICAMENTOS FORMULADOS A LA POBLACIÓN POBRE NO AFILIADA AL SGSSS Y POBLACIÓN EN SITUACIÓN DE DESPLAZAMIENTO DEL MUNICIPIO DE FUENTEDEORO
Zuker final.indd ns.inddNATURE Vol 444 16 November 2006 doi:10.1038/nature05401
The receptors and cells for mammalian tasteJayaram Chandrashekar1, Mark A. Hoon2, Nicholas J. P. Ryba2 & Charles S. Zuker1 The emerging picture of taste coding at the periphery is one of elegant simplicity. Contrary to what was
generally believed, it is now clear that distinct cell types expressing unique receptors are tuned to detect each
of the five basic tastes: sweet, sour, bitter, salty and umami. Importantly, receptor cells for each taste quality
function as dedicated sensors wired to elicit stereotypic responses.
Our sensory systems are responsible for generating an internal represen- The anatomical substrates and units of taste detection are taste-recep- tation of the outside world, including its chemical (taste and olfaction) tor cells (TRCs; Fig. 1). TRCs are assembled into taste buds, which are and physical (mechanical, sound, vision and temperature) features. In distributed across different papillae of the tongue and palate epithelium. this review we examine recent advances in our understanding of the How are the different tastes detected, and how is taste quality represented? biology of taste, focusing on receptors, cells and the logic of taste cod- In the simplest scenario, sweet, bitter, sour, salty and umami tastants ing at the periphery.
would each be recognized by different cells expressing specialized recep- Taste is in charge of evaluating the nutritious content of food and pre- tors. Coding at the periphery could then rely on straightforward labelled venting the ingestion of toxic substances. Sweet taste permits the identi- lines (that is, independent sweet, bitter, sour, salty and umami signals) fication of energy-rich nutrients, umami allows the recognition of amino to transform tastant quality into neural signals (Fig. 2a). In an alterna- acids, salt taste ensures the proper dietary electrolyte balance, and sour tive view, and the prevailing model for the past two decades1–3, TRCs and bitter warn against the intake of potentially noxious and/or poison- were proposed to be broadly tuned across taste modalities (Fig. 2b, c). ous chemicals. In humans, taste has the additional value of contributing In this case, it would be expected that individual TRCs would express to the overall pleasure and enjoyment of a meal. Surprisingly, although different families of taste receptors, and that tastant recognition would we can taste a vast array of chemical entities, it is now generally accepted result from decoding of the combined activity of various classes of such that, qualitatively, they evoke few distinct taste sensations: sweet, bitter, broadly tuned TRCs (the ‘across-fibre pattern' of coding)4,5. The recent sour, salty and savoury (or umami). Although this repertoire may seem identification of cells and receptors mediating sweet, bitter, umami and modest, it has satisfactorily accommodated the evolutionary need for sour taste (Figs 3, 4; Table 1) has generated powerful molecular tools that an effective and reliable platform to help recognize and distinguish key can be used to devise rigorous tests to distinguish between these models dietary components.
and establish the basis of taste coding at the periphery.
Figure 1 Taste-receptor cells,
buds and papillae. a, Taste buds
(left) are composed of 50–150
TRCs (depending on the species),
distributed across different
papillae. Circumvallate papillae
are found at the very back of the
tongue and contain hundreds
(mice) to thousands (human) of
taste buds. Foliate papillae are
present at the posterior lateral
edge of the tongue and contain a
dozen to hundreds of taste buds.
Fungiform papillae contain one
or a few taste buds and are found
in the anterior two-thirds of the
tongue. TRCs project microvillae
to the apical surface of the taste
bud, where they form the ‘taste
pore'; this is the site of interaction
with tastants. b, Recent molecular
and functional data have revealed
that, contrary to popular
belief, there is no tongue ‘map':
responsiveness to the five basic
modalities — bitter, sour, sweet,
salty and umami — is present in
all areas of the tongue6,8,9,32,78.
1Howard Hughes Medical Institute and Departments of Neurobiology and Neurosciences, University of California at San Diego, La Jolla, California 92093-0649, USA. 2National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
2006 Nature Publishing Group
Zuker final.indd NS.indd 288 Zuker final.indd NS.indd 288 3/11/06 5:21:09 pm 3/11/06 5:21:09 pm NATURE Vol 444 16 November 2006 Figure 2 Encoding of taste qualities at the periphery. There are two opposing views of how taste qualities are encoded in the periphery. a, In the labelled-
line model, receptor cells are tuned to respond to single taste modalities — sweet, bitter, sour, salty or umami — and are innervated by individually tuned
nerve fibres. In this case, each taste quality is specified by the activity of non-overlapping cells and fibres. b, c, Two contrasting models of what is known as
the ‘across-fibre pattern'. This states that either individual TRCs are tuned to multiple taste qualities (indicated by various tones of grey and multicoloured
stippled nuclei), and consequently the same afferent fibre carries information for more than one taste modality (b), or that TRCs are still tuned to single
taste qualities but the same afferent fibre carries information for more than one taste modality (c). In these two models, the specification of any one
taste quality is embedded in a complex pattern of activity across various lines. Recent molecular and functional studies in mice have demonstrated that
different TRCs define the different taste modalities, and that activation of a single type of TRC is sufficient to encode taste quality, strongly supporting
the labelled-line model.
Humans and mice show some prominent differences in their ability The sweetness of sugar and the pleasure it evokes are so familiar to us to taste certain artificial sweeteners and intensely sweet proteins — for that they almost seem to be physical properties of sucrose rather than example, mice cannot taste aspartame or monellin. Notably, introduction a representation of neuronal firing in the brain. This tight relationship of the human T1R2 receptor into mice significantly changes their sweet between sensory quality, positive hedonic value and behavioural accept- taste preferences to a human-like response profile15, proving that species ance richly illustrates how sweet taste detection and perception evolved differences in sweet taste sensitivity and selectivity are a direct reflection to help with the recognition of the most basic and fundamental sources of T1R-sequence variation between species. How does a single receptor of metabolic energy.
complex respond to such a wide range of sweet-tasting compounds, The attractive taste modalities, sweet and umami, are mediated by a from simple six-carbon sugars to guanidinoacetic acids and even large small family of three G-protein-coupled receptors (GPCRs) — T1R1, peptides21 and polypeptides? Recently, biochemical studies of human, T1R2 and T1R3 — that is distantly related to metabotropic glutamate, rodent and chimaeric human–rodent T1R2+3 receptors have shown pheromone, extracellular-calcium sensing and γ-aminobutyric-acid that diverse classes of sweet-receptor ligands actually require different type B receptors6–15. These GPCRs assemble into either homodimeric domains of the receptor complex for recognition22–24, thus providing a or heterodimeric receptor complexes16, and are characterized by the simple solution to this puzzle. Together, these genetic, functional and presence of long amino-terminal extracellular domains that are believed biochemical studies have amply validated the role of the T1R2 and T1R3 to mediate ligand recognition and binding17.
subunits in sweet-tastant recognition, and demonstrated the importance The critical role of T1Rs in sweet taste detection and perception of heteromerization in receptor function.
emerged from an ensemble of studies, including the characterization Definitive proof that T1R2+3 is the principal mammalian sweet of T1R expression profiles, the analysis of naturally occurring sweet taste receptor was obtained from studies of T1r2- and T1r3-knockout receptor mutants (and the identification of species-specific differences mice15,25 (Fig. 3). Homozygous mutants for either receptor subunit show in sweet taste preferences), functional experiments in cell-based assays, a devastating loss of sweet taste — all behavioural and electrophysiogical and the generation of genetically modified mouse lines. responses to artificial sweeteners, d-amino acids and low to moderately T1Rs are expressed in subsets of TRCs, and their expression pattern high concentrations (up to 300 mM) of natural sugars are abolished15,25. defines three cell types: TRCs co-expressing T1R1 and T1R3 (T1R1+3 However, these animals retain very small, albeit measurable, responses cells), TRCs co-expressing T1R2 and T1R3 (T1R2+3 cells) and TRCs to very high concentrations of sugars. Importantly, a T1r2;T1r3 double containing T1R3 alone8. What do these cells do? More than 30 years ago, knockout completely eliminated these remaining sweet responses15, genetic studies of sweet taste in mice identified a single principal locus unequivocally demonstrating the essential role of T1Rs in all sweet taste that influences responses to several sweet substances18,19. This locus, detection and perception. Unexpected corroboration of the fundamen- known as Sac, determines threshold differences in the ability of some tal requirement of T1Rs for sweet taste came from the recent discovery strains to distinguish sucrose- and saccharin-containing solutions from that cats (all felidae from the common house kitten to the tiger) carry a water19. The Sac locus was recently shown by linkage analysis8,11–14,20 naturally occurring deletion in their T1r2 gene26, providing a molecular and genetic rescue8 to encode T1R3, thus implicating a member of the explanation to the striking, and long-standing, observation that cats do T1r gene family in sweet taste detection. Indeed, functional expression not respond to sweets.
studies in heterologous cells revealed that T1R3 combines with T1R2 (T1R2+3) to form a sweet taste receptor that responds to all classes of Umami taste
sweet tastants, including natural sugars, artificial sweeteners, d-amino Most mammals are robustly attracted to the taste of a broad range acids and intensely sweet proteins8,10. These results validated the T1R2+3 of l-amino acids15,27–29. In humans, however, just two amino acids heteromer as a sweet receptor, and suggested that T1R2+3 cells are the — monosodium glutamate (MSG) and aspartate — evoke the unique sweet-sensing TRCs (see below).
savory sensation known as umami (whose Japanese characters can be 2006 Nature Publishing Group
Zuker final.indd NS.indd 289 6/11/06 10:02:57 am NATURE Vol 444 16 November 2006 glutamate and l-amino acids15 (but see also ref. 25). Together, these results firmly established the T1R1+3 heteromeric GPCR complex as the mammalian umami taste receptor and provided a striking example of heteromeric GPCRs radically altering their selectivity according to a combinatorial arrangement of subunits (sweet T1R2+3 versus umami T1R1+3). They also revealed that sweet and amino-acid (umami) taste — two chemosensory inputs that trigger behavioural attraction — share a common receptor repertoire and evolutionary origin.
In contrast to sweet and umami taste, which evolved to recognize a lim-
ited subset of nutrients, bitter taste has the onerous task of preventing
the ingestion of a large number of structurally distinct toxic compounds. Remarkably, despite the vastness of this repertoire, these compounds all evoke such a similar sensation that we simply know them as ‘bit-ter'. These observations suggest that bitter taste receptors are probably encoded by a large family of genes, and that the bitter sensation evolved to allow recognition of a wide range of chemicals, but not necessarily to distinguish between them.
Bitter taste is mediated by a family of 30 highly divergent GPCRs (the T2Rs)32,33. T2R genes are selectively expressed in subsets of TRCs distinct from those containing sweet and umami receptors32, and are clustered in regions of the genome genetically linked to bitter taste in humans and mice32–35. A large number of T2Rs have been shown to function as bitter taste receptors in heterologous expression assays36–40, and several have distinctive polymorphisms that are associated with significant variations in sensitivity to selective bitter tastants in mice36, chimpanzees41 and humans42. Proof that T2Rs are necessary and sufficient for bitter taste came from knockout and misexpression studies in mice. On the one hand, animals lacking a specific T2R (for example, T2R5, the candidate cycloheximide receptor), exhibited a marked and selective loss of their ability to taste the cognate bitter compound43 (Fig. 3). On the other hand, mice engi- Figure 3 Sweet, umami, bitter and sour are mediated by specific receptors
neered to express the human candidate receptors for PTC (phenylthio- and cells. The traces show recordings of tastant-induced activity in nerves
carbamide) and salicin, two bitter substances that mice do not normally innervating the tongue in wild-type and various gene-knockout (KO) mice
respond to, became vigorously averse to these two chemicals43. These or cell ablation studies (Pkd2l1-DTA). T1R1+3 functions as the umami
results demonstrated that T2Rs are necessary and sufficient for selective receptor, T1R2+3 is the sweet receptor, T2Rs are bitter receptors (T2R5 is a
responses to bitter tastants, and validated T2Rs and T2R-expressing cells high-affinity cycloheximide receptor), PKD2L1 is a candidate sour receptor,
as the in vivo mediators of bitter taste detection and perception. In addi- and PLC-β2 is the effector and TRPM5 the transduction channel of sweet,
umami and bitter pathways. Note the extraordinarily specific taste deficits
tion, the fact that the bitter taste responses of mice can be humanized (red traces) in each genetically altered mouse line. Pkd2l1-DTA refers to
by introducing human taste receptors illustrated an important feature animals expressing diphtheria toxin in PKD2L1 cells.
of T2Rs and bitter taste: selectivity and sensitivity differences to bitter compounds between species is likely to be a reflection of sequence dif-ferences in their respective T2R repertoires44,45.
translated as ‘delicious flavour')30, perhaps best exemplified in western A remarkable feature of bitter-receptor biology was exposed by the dis- cuisine by the taste of meaty broths. A salient feature of amino-acid taste covery that most, if not all, T2Rs are expressed in the same TRCs32. This in animals, and umami taste in humans is their impressive potentiation implied that individual T2R-expressing cells may function as broadly by purine nucleotides (such as IMP and GMP)31. This feature has been tuned sensors for all bitter chemicals but might have very limited, if any, cleverly commandeered by the food industry as a means of enhancing discrimination. In fact, it would not be unreasonable to imagine that the flavour of a wide range of products, and was expected to be a bio- although animals must be able to detect many bitter compounds, they chemical hallmark of the authentic umami receptor.
have no need to distinguish between them qualitatively. Indeed, recent Cell-based expression studies have shown that the rodent T1R1 and studies in mice have confirmed that T2R-expressing cells operate as T1R3 GPCRs combine to form a broadly tuned l-amino-acid receptor9. universal bitter sensors43,46, and that, although mice and rats can distin- These results validated T1R1+3 as an amino-acid taste receptor, and the guish differences in intensity between bitter tastants, they are incapable T1R1+3-expressing cells as candidate umami-sensing cells. Interest- of discriminating between them47. Of course, it would be unreasonable ingly, in cell-based assays, the human T1R1+3 complex functions as a to expect that different bitter TRCs express the same T2R proteins at much more specific receptor, responding selectively to monosodium identical levels, and thus individual bitter-sensing cells can be predicted glutamate and aspartate (as well as to the glutamate analogue L-AP4), to vary in their sensitivity to bitter tastants but still be able to respond with sensitivity that recapitulates human psychophysical thresholds to the full repertoire.
for umami taste9,10. In addition, as would be predicted for the genuine umami receptor, both the rodent and human T1R1+3 heterodimers Signalling downstream of T1Rs and T2Rs
showed strong potentiation in response to purine nucleotides9,10. Signalling cascades downstream of taste receptors have been the subject Final proof that T1R1+3 functions in vivo as the amino-acid (umami) of intense speculation over the years, with most models hypothesizing taste receptor was obtained from the study of T1r1- and T1r3-knock- a surprising diversity of pathways and strategies48–50. This proposed out mice15,25 (Fig. 3). Homozygous mutants lacking either the T1R1 or complexity contrasted sharply with the demonstrated simplicity of the T1R3 subunit showed an overwhelming loss of umami taste, includ- signalling pathways of other senses, such as olfaction, in which hun- ing all responses to IMP and behavioural attraction to monosodium dreds of distinct receptors share an identical transduction cascade51. 2006 Nature Publishing Group
Zuker final.indd NS.indd 290 Zuker final.indd NS.indd 290 3/11/06 5:21:32 pm 3/11/06 5:21:32 pm NATURE Vol 444 16 November 2006 Sure enough, recent results have demonstrated that the receptors for hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels71, sweet, bitter and umami taste, although expressed in separate subsets acid-sensing ion channels (ASICs)72, potassium (K2P) channels73,74 of cells8, all signal through a common pathway to transduce tastant and H+-gated calcium channels75, as well as the involvement of Na+/H+ recognition into cell activation46 (but see also ref. 52). exchangers76 and acid inactivation of K+ channels77. However, recent The current data suggest that tastant binding to T1Rs or T2Rs acti- genetic and functional studies have greatly simplified the quest for the vates the heterotrimeric G proteins gustducin53 or Gα (ref. 54) leading sour receptor by demonstrating that a member of the TRP ion-channel to the release of the Gβγ subunits46,55 and the subsequent stimulation of family, PKD2L1, demarcates sour-sensing TRCs78. PKD2L1 is selectively phospholipase Cβ2 (PLC-β2)46,56. Activation of PLC-β2 hydrolyses phos- expressed in a population of TRCs distinct from those mediating sweet, phatidylinositol-4,5-bisphosphate to produce the two intracellular mes- umami and bitter tastes78,79, further substantiating the cellular segrega- sengers inositol-1,4,5-trisphosphate and diacylglycerol, and ultimately tion of taste modalities at the periphery.
leads to the gating of the taste-transduction channel (the transient recep- Proof that PKD2L1-expressing cells function as the acid receptors in tor potential (TRP) protein TRPM5)46,57. As expected from this model, the taste system came from conclusive genetic-ablation experiments. mouse knockouts of gustducin58,59, PLC-β2 (refs 46, 60) or TRPM5 (refs The targeting of diphtheria toxin to PKD2L1-expressing cells of the 46, 52) have major deficits in sweet, umami and bitter tastes (Fig. 3). tongue produced animals with a specific and total loss of sour taste78 Importantly, salty and sour tastes remain unimpaired in all cases46, dem- (Fig. 3). These results validated PKD2L1 TRCs as the sole acid-sensing onstrating that these two modalities use a different signalling pathway cells and implicated the PKD2L1 ion channel as the candidate compo- and operate independently of sweet, umami and bitter tastes.
nent of the sour taste (pH) receptor78,80. The further demonstration that Are other pathways important in the detection and perception of these sour-deficient mice have normal salt responses indicates that salt sweet, bitter and umami tastes? We would expect signalling molecules taste also must be mediated by an independent population of TRCs (see representing many different transduction cascades to be present in most Fig. 3 and below).
types of cell, including TRCs56,61–66. However, their mere presence does Although sweet, umami and bitter sensing are primarily required in not imply that they must be involved in taste transduction50. Compre- the taste system, acid sensing is also important in a number of other hensive physiological and genetic studies will be required to assess what processes, including the monitoring of CO levels in the blood81 and role, if any, they have in taste signalling. It would be interesting if second the internal state of the cerebrospinal fluid and brain82. Consequently, messengers from a number of pathways modulate taste signals, both it may be predicted that PKD2L1 might also function in other physi- at the receptor and downstream levels, and thus provide a platform to ological settings. Indeed, Huang and colleagues78 showed that PKD2L1 shape taste responses as a function of various cues and cellular states. is expressed in a selective population of neurons contacting the cen- Intriguingly, activation of the TRPM5 transduction channel was recently tral canal of the spinal cord that fire in response to minor changes in shown to be strongly temperature dependent67, at a range within the nor- proton concentration. These results suggest that these neurons func- mal function of TRCs (15–35 ºC). Talavera and colleagues67 proposed tion as sentinels of cerebrospinal and ventricular pH, and bring forth that this property of the channel may underlie some of the effects of a surprising unity in the cellular basis of pH sensing in very different temperature on taste detection and, ultimately, perception67. It would be rewarding to engineer animals expressing TRPM5 channels with modified temperature profiles and determine the behavioural and physi- Taste coding at the periphery
ological impact of such changes on taste responses.
Several electrophysiological and calcium-imaging-based studies in rats and mice have reported that individual TRCs are tuned to various taste Salt and sour tastes
modalities4,83–85 and have proposed that encoding of taste quality at the A number of studies have suggested that salty and sour tastants modu- periphery must use an across-fibre pattern of activity (Fig. 2). However, late taste-cell function by direct entry of Na+ and H+ through specialized the discovery that sweet, umami, bitter and sour (and, by extrapola- membrane channels on the apical surface of the cell. In the case of salt, tion, salt) taste cells are segregated into non-overlapping populations TRC activation is believed to be mediated at least in part by the entry of expressing distinct receptors (Fig. 4) demands a revision of this model. Na+ through amiloride-sensitive Na+ channels68,69. However, the identity We review three lines of investigation demonstrating that the TRCs of the salt ‘receptor' remains speculative and highly controversial68,70.
defined by T1Rs, T2Rs and PKD2L1 function as highly dedicated sen- A broad range of cell types, receptors and mechanisms have been sors for sweet, umami, bitter and sour tastes, strongly arguing, instead, proposed to be responsible for sour taste. These include the activation of for a labelled-line model of coding across all taste modalities.
Figure 4 Summary of receptors for umami, sweet, bitter and sour tastes. Schematic representation of taste receptors (and candidate receptors) mediating
four of the five basic taste modalities. Although not indicated in the figure, responses to high concentrations of sugars, but not other sweet tastants, are also
detected by T1R3 alone15. The grey T2R receptor is designed to illustrate the possibility that T2Rs, much like T1Rs, may function as heteromeric complexes.
Similarly, the grey receptor next to PKD2L1 depicts a PKD1-family member as a candidate partner78–80.
2006 Nature Publishing Group
Zuker final.indd NS.indd 291 Zuker final.indd NS.indd 291 3/11/06 5:26:27 pm 3/11/06 5:26:27 pm NATURE Vol 444 16 November 2006 Table 1 Tastant selectivity of candidate mammalian taste receptors
aversion mediated by sweet- or bitter-sensing cells, thus strongly sub-stantiating a labelled-line model of taste coding at the periphery. A final Class of tastant Examples of tastants corollary to these findings is that expression of a sweet receptor in bit- ter cells should trigger behavioural aversion to sweet tastants, whereas l-Glutamate, L-AP4, expression of a bitter receptor in sweet cells should result in attraction glycine*, l-amino acids* to the bitter compound. Indeed, Mueller43 engineered animals express- Nucleotide enhancers ing a bitter receptor in sweet cells (Fig. 5) and these mice showed strong Sweet T1R2+T1R3 Sugars† Sucrose, attraction to the cognate bitter compounds. Thus, the ‘taste' of a sweet or bitter compound (in other words, the perception of sweet or bitter) Artificial sweeteners Saccharin, acesulfame-K, is a reflection of the selective activation of T1R- versus T2R-express- ing cells, rather than a property of the receptors or even of the tastant d-Phenylalanine, d-alanine, d-serine (also some proteins‡ Monellin, Bitter, sweet and sour
Using a conceptually complementary approach to the functional rescue of subsets of TRCs described above, Huang and colleagues78 eliminated entire populations of TRCs by genetically targeting expression of diph- theria toxin (DTA) to defined subsets of taste cells. Remarkably, animals expressing DTA in T1R2-, T2R- or PKD2L1-expressing cells showed extraordinarily specific taste deficits, with each exhibiting a marked loss of only a single taste quality (sweet, bitter and sour, respectively). Taken together, these studies reveal three fundamental features of taste Other toxic/noxious Quinine, strychnine, atropine coding at the periphery. First, they prove the functional segregation of individual taste modalities at the cellular level (as proposed in the Citric acid, tartaric acid, original receptor expression studies8,46,78). Second, they show the abso- acetic acid, hydrochloric acid lute requirement of T1R2-, T2R- and PKD2L1-cells for sweet, bitter *Preferentially activates mouse but not human receptors. and sour taste. Finally, they demonstrate that animals recognize and †High concentrations of sugars, but not other sweet tastants, can also be detected by T1R3 alone15. ‡Activates human but not mouse receptors and does not elicit behavioural responses in wild-type respond to taste cues (that is, encode and decode signals) without the need for combinatorial patterns of activity at the periphery (across- §About 30 T2Rs are involved in bitter-tastant recognition. fibre models).
¶Mouse T2Rs; all others shown are human. There are 25 human and 35 mouse T2R bitter-taste receptors. For illustrative purposes we have included receptor–ligand matches for a number of de-orphaned T2Rs (for example, mouse T2R5 is the receptor for the protein synthesis inhibitor The exciting journey from detection to perception
The discovery that individual taste modalities are encoded by different TRCs should make it possible to mark the connectivity pathway for each taste quality individually. As a result, it should be possible to trace PLC-β2 is required for sweet, umami and bitter tastes46,60, so Plc-β2- defined lines of information from the tongue to the cortex to under- knockout animals are blind to stimuli from any of these three taste stand not only where these signals go, but where and how they combine qualities (Fig. 3). If individual TRCs were tuned to a single taste quality, in the circuitry to choreograph taste and flavour.
then restoring PLC function to a unique population of TRCs in Plc- Two recent reports have provided promising avenues to explore knockout animals (for example T2R cells) should restore taste to a single the connectivity between TRCs and central neuronal stations. In the taste modality (bitter taste in this example). By contrast, if these same cells were broadly tuned to sweet, amino-acid and bitter tastes, then restoring function to T2R cells (by expressing PLC) would restore taste to multiple modalities. Recently, Zhang and co-workers46 showed that mice engineered to rescue PLC-β2 function exclusively in T2R-express- ing cells respond normally to bitter tastants but do not taste sweet or amino-acid stimuli. This ‘selective rescue' experiment demonstrated both that activation of T2R cells is sufficient for normal bitter taste and that bitter taste is encoded independently of sweet and amino-acid tastes, with TRCs not broadly tuned across these modalities.
Bitter and sweet
To investigate the basis of sweet and bitter tastant recognition and Wild-type control coding, Zhao et al.15 and Mueller and colleagues43 engineered mice that expressed a modified κ-opioid receptor (RASSL; receptor activated solely by a synthetic ligand86) in either sweet or bitter cells. Animals expressing Preference ratio (%) RASSL in sweet cells become selectively attracted to the synthetic-opi- oid-agonist spiradoline, a normally tasteless compound, demonstrating that activation of sweet-receptor-expressing cells, rather than the sweet receptor itself, results in the perception of sweetness. More importantly, Bitter tastant (mM) these results showed unequivocally that activating a single cell type is sufficient to trigger specific taste responses. Does the same logic apply to Behavioural attraction and aversion are mediated by dedicated
taste-receptor cells. Targeted expression of a novel bitter receptor to bitter
bitter taste? Mueller and co-workers43 tested this idea by generating mice (T2R-expressing) cells results in dose-dependent aversion to the specific
in which the same RASSL receptor was targeted to bitter taste cells. Such bitter tastant (open blue squares). In marked contrast, directing expression
mice showed marked aversion, rather than attraction, to spiradoline. of the same receptor to sweet cells produces animals that are strongly
Together, these results demonstrated that a combinatorial pattern of attracted to this bitter tastant (filled red circles). Control animals lacking
activity (across-fibre pattern) is not needed to account for attraction or the receptor (filled grey circles) are indifferent to the tastant.
2006 Nature Publishing Group
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npg.nature.com/reprintsandpermissions. The authors declare no competing 85. Richter, T. A., Caicedo, A. & Roper, S. D. Sour taste stimuli evoke Ca2+ and pH responses in financial interests. Correspondence should be addressed to C.S.Z. or N.J.P.R. mouse taste cells. J. Physiol. (Lond.) 547, 475–483 (2003).
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Balancing Brain Chemistry to Treat Depression By Liz Butler This article first appeared in CAM magazine Introduction It is taking a long time for the scientific community to fully accept that what a person eats can influence their mental state but in the last few decades progress in this area has been rapid. Taking a very basic view of the subject there can be no doubt that nutrition is intimately involved with mental health as the brain and its chemical messengers are ultimately derived from food. Convincing doctors used to the traditional approach of treating mental disturbance and depression (drugs or psychotherapy) to consider the nutritional treatment approach is more difficult than simply pointing out this fact. Fortunately there is now a large amount of research supporting the view that nutrition has a role to play in promoting mental health, this article will review some of this research. It is well established that neurotransmitter imbalances can lead to mental dysfunction and depression and in fact most drugs currently being used in this area of disease aim to restore chemical balance within the nervous system (1). As some of the research mentioned in this review shows, certain nutritional factors may be able to promote chemical normality in the same way as current pharmaceutical treatments but without the side effects associated with drug therapy. Within a discussion about depression there must be some mention of genetic factors as there is no denying that the risk of developing depression, particularly a severe form, is influenced by genetics (2). It is likely that certain people are born with a predisposition to biochemical imbalances within the brain and then an inadequate nutrient intake compounds the problem. Eventually the situation deteriorates until there is expression of disease. What this means however, is that even disease with a genetic component may possibly be reversed given the correct nutrients to balance brain chemistry. Brain chemistry The brain is composed of about 100 billion neurones, the cells of the nervous system that communicate messages to each other, making up what is termed grey matter. The processes that extend from the cells to meet up with other cells constitute the white matter of the brain. Amongst the neurones are cells called neuroglia. Their role is to support, protect, and repair the neurones. Neurotransmitters are chemical substances that pass between neurones relaying messages. Examples include acetylcholine, histamine, adrenaline, noradrenaline, dopamine, and serotonin. All of these are well-studied neurotransmitters, and the effects of too much, or too little on the mental state are well observed. In addition neuromodulators and neurohormones are further classes of chemicals that affect nervous function. Neuromodulators modulate signal transmission either pre- or post-synaptically and neurohormones behave like neurotransmitters but act at a site distant