05_ Chemical Senses: Taste
Pathway of taste and smell
All taste fibers synapse in the rostral portion of the nucleus tractus solitarii. From there second order neurons project to the thalamus. From the thalamus the taste information reaches the somatosensory and the primary taste cortex. Cortical neurons which project from there to the amygdala (and other areas of the limbic system as well as the hippocampus) and to the hypothalamus are important for the affective component of taste (amygdala) and the initiation of autonomic reflexes (hypothalamus). The orbitofrontal cortex is a sensory hub (hot spot) in the brain where all sensory modalities come together. The extensive overlap with the processing of olfactory information explains the close relationship of taste and smell.
Capsaicinoid effects
Capsaicinoids are the pungent principle of hot peppers that have been used as pungent spices, in particular, in hot climates, but also in traditional medicine for centuries. Capsaicin is the most common capsaicinoid. It increases energy expenditure, enhances lipolysis and fatty acid oxidation, and has been shown to decrease food intake. Capsaicin exerts its actions through the transient receptor potential vanilloid receptor-1 (TRPV1) TRPV1 on sensory neurons in the oral cavity mediate the pungency of capsaicin. Capsaicin is neurotoxic in high concentrations. TRPV1 is a calcium channel that is ubiquitously expressed by sensory neurons and activated by different noxious stimuli. The activation of TRPV1 on sensory afferent neurons by capsaicin stimulates sympathetic efferents.
The epithelial Na-channel (ENaC) is necessary for high sensitivity responses to sodium
ENaC knockout mice show a complete loss of the responses to low concentrations of NaCl, demonstrating that ENaC is the sodium sensor in rodents. It is still unclear whether there are additional sodium sensing mechanisms in humans. Importantly, the knockout mice retain all responses to non-ssodium salts, demonstrating that taste responses to different salts are mediated by genetically separable components.
Genetic variants determining individual differences
Genetic polymorphisms in the TAS1R genes -> the two subunits of the sweet receptor TAS1R-independent polymorphisms in the GNAT3 gene -> subunit of gustducin Polymorphisms in the dopamine D2 receptor -> CNS processing of the taste information
The sweet receptor
Many sweet substances bind to the venus fly trap motif (VFTM) in the extracellular domain of the sweet receptor The taste receptor-specific G-protein gustducin (green) mediates the activation of a phospholipase (PLC) This opens Ca++-channels in the ER (yellow) and, hence, results in an increase in intracellular Ca++, which depolarizes the membrane and ultimately causes the release of ATP
Phenylthiocarbamide (PTC) or phenylthiourea (PTU)
People have very different sensitivity, from very bitter to virtually tasteless, depending on the genetic makeup of the taster. The ability to taste PTC is often treated as a dominant genetic trait, although inheritance and expression of this trait are somewhat more complex. The TAS2R38 is the receptor for PTC and PROP. The differences between the taster and non-taster form lie in the aa residues at positions 49, 262 and 296; the functional allele of the receptor contains a proline, alanine and valine (PAV), while the nonfunctional allele of the receptor contains an alanine, valine and isoleucine (AVI) at these positions. Several studies link the ability to taste thiourea compounds to dietary habits. Much of this work has focused on PROP, a compound related to PTC that has lower toxicity. A supertaster has more of the ability to taste PTC. Onh the other hand, heavy cigarette smokers are more likely to have high PTC and PROP thresholds. The TAS2R38 is also prominently expressed in upper airway epithelium, and recent findings link PTC sensitivity, i.e., the common polymorphisms of the TAS2R38 gene to significant differences in the ability of upper respiratory cells to clear and kill bacteria. Thus, the TAS2R38 genotype correlates with human sino-nasal gram-negative bacterial infection.
Special features of the chemical senses
Phylogenetically very old: Chemosensation is considered to be the primary sensory modality in all metazoans. Stimuli do not fit into a physical continuum: Unlike sound or electromagnetic waves that we can hear or see, and where different tones or colors only differ by wavelength and frequency, chemosensory stimuli can be vastly different. Affective component stronger than for other sense: The processing of chemosensory stimuli involves more parts of the limbic system than the processing of other sensory modalities.
Prop sensitivity reduces intake of bitter vegetables
Prop sensitivity also influences the acceptance of other foods, in particular fat selection in girls
Brain areas involved in reward processing
Reward system proper: Amygdala Nucleus Accumbens Orbitofrontal Cortex Ventral Pallidum Ventral Tegmental Area Associated areas involved in motivation: Anterior Cingulate Cortex Caudate, Putamen Hippocampus Hypothalamus Insula Prefrontal Cortex
TRP channels and their common activators
Schematic representation of the thermo TRPs that function in temperatures ranging from nixious heat to noxious cold. Proposed membrane topology and functionally important domains are represented. They include 6 putative transmembrane units with a proposed pore region between transmembrane domains 5 and 6.
Why do we all like sweet?
Sheer physiology D-glucose is preferred fuel for neurons -> motivation to maintain high levels of circulating glucose Low storage capacity for glucose -> need for continuous sugar procurement and, if available, consumption Specialized sugar receptors in oral cavity -> connected to brain reward circuitries promoting ingestion
Ion channel receptors pathways
Sour and salty taste are mediated by ion channel type receptors. In the case of sour taste, the most likely candidate is a heterodimer of PKD1L3/PKD2L1. Genetic elimination of cells expressing PKD2L1 substantially reduces gustatory nerve responses to sour taste stimuli. Patients with sour ageusia, but not sour normal individuals, lack the expression of mRNAs for PKD1L3 and PKD2L1. In the case of salt taste, the epithelial sodium ion channel is believed to be a receptor because amiloride, an epithelial sodium channel blocker, reduces taste cell, neural, and behavioral responces to NaCl. It is clear, however, that other mechanisms contribute to salt taste in particular in humans. When channel type receptors are activated by taste compounds, taste cells are depolarized and elicit action potentials through voltage-gated sodium channels. ATP is the most likely transmitter, but serotonin could also play a role
Trigeminal sensitivity
Spicyness is NOT mediated by the gustatory system. Spices act on the TRP channels on free nerve endings of the trigeminal system, which has mainly protective functions. Many of these trigeminal nerve endings do, however, surround the taste buds. Several mechanism have been proposed for whyy humans eat spicy food: hygiene, to keep animals away from the food, because of a learned preference (thermoregulatory effect), etc.
Supertasters vs. Nontasters
Supertasters experience the sense of taste with greater intensity than average. Some 35% of women and 15% of men are supertasters. Supertasters are more likely to be of Asian, African, and South American descent. The cause of this heightened response is unknown, although it is thought to be related to the presence of the TAS2R38 gene, the ability to taste PROP and PTC, and at least in part, due to an increased number of fungiform papillae. Any evolutionary advante to supertasting is unclear. In some environments, a heightened response to bitterness coul represent an advantage in avoiding potentially toxic plant alkaloids. In other environments, increased response to bitterness may have limited the range of palatable foods. It may be a cause of picky eating, but picky eater are not necessarily supertasters, and vice versa.
Primary (basic) tastes
Sweet Sour Salty Bitter Umami (mono-sodium glutamate, aspartate) Primary tastes mean that everything that we can taste, i.e., detect with our gustatory system, is a combination of these 5 basic tastes Cave 1: what we call "taste" is usually more complex and comprises the full spectrum of the orosensory experience with food! Cave 2: there is quite some discussion these days that we may also have a taste for fat (sixth basic taste)
Neonatal response to taste
Sweet is accepted. Sweet foods are easily accepted (liked and eaten). Universal hedonic reaction: Tongue protrusions to sweet Bitter is rejected Bitter foods such as vegetables are less easily accepted (disliked and avoided) Universal aversion: Gapes to bitter Humans as all mammals have an innate preference for sweet and an innate aversion for bitter taste. This is usually supposed to be related to the fact that mothers milk tastes sweet and that sweet taste in nature is often an indicator of readily available energy, whereas bitter taste can indicate toxic substances. Umami is usually also preferred and sour mostly avoided. The reactions to salt depend on the concentration, with high concentrations producing avoidance and low concentrations neutral responses. Salt sensitivity may show up slightly later than sensitivity to other taste stimuli. it is important to note that these innate reactions can of course change based on experience/learning.
G-Protein coupled receptors pathways
Sweet, umami, and bitter tastes are mediated by different GPCRs, but use a common signaling pathway after activation of these receptors. Tastant binding to sweet, umami, and bitter receptors activates a heteromeric G-protein and leads to subsequent stimulation of PLCb2. Activation of PLCb2 produces IP3, a ligand for the IP3 receptor in the ER. Then calcium is released from the ER and the increase in intracellular calcium opens transient receptor potential channel M5 (TRPM5) to depolarize the taste cells. Such depolarization leads to the generation of action potentials in taste cells through the massive inflow of sodium through voltage-gated sodium channels (VGSC). This causes transmitters such as ATP to be released from synaptic vesicles to bind to their receptors on primary neurons.
G-protein coupled receptors
Sweeteners T1R2+T1R3 L-amino acids T1R1+T1R3 "Umami" bitters T2Rs Homodimeric or heterodimeric GPCRs transduce umami, sweet and bitter taste. Interestingly, the attractive taste qualities sweet and umami are encoded by heterodimeric variations of only three GPCRs (T1R1, T1R2, T1R3) Responses to high concentrations of sugars can also be detected by T1R3 alone.
Taste cells can encode behavioral responses!
Targeted expression of a novel bitter receptor to bitter (T2R-expressing) cells results in dose-dependent aversion to the specific bitter tastant. In marked contrast, directing expression of the same receptor to sweet cells produces animals that are strongly attracted to this bitter tastant. Control animals lacking the receptor are indifferent to the tastant. This demonstrates that the reaction to tastants - from the taste receptor to the behavior - is basically "hard wired", which also strongly supports the labelled line model.
Taste receptor cells (TRC), -buds, and papillae
Taste buds consist of 50-150 TRC, 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. TRC carry microvilli on the apical surface that are exposed in the "taste pore"; this is the site where tastants can act on the TCR. Recent molecular and functional data revealed that, contrary to popular belief, there is no tongue map: responsiveness to the five basic modalities is present in all areas of the tongue. Nerve fiber enter from the bottom and form synaptic contacts with only a portion of the taste receptor cells (they seem to be electrically coupled through gap junctions). The life span of TRC is about 10 days.
Taste receptors
Taste receptors for stimuli generating different basic taste qualities do not appear to be co-expressed in the same taste bud cells. TRCs are Secondary Sensory Cells, they are modified epithelial cells. Individual TRCs primarily respond to single taste modalities. TRC also express receptros for various metabolic hormones, such as glucagon, GLP-1, ghrelin, leptin, etc
Taste + Smell = Flavor
The chemical senses are critical for the control of eating - taste and smell determine what we eat and warn us of potentially dangerous food components. Of course, in addition to taste and smell, somato-sensory, thermosensitive and non-specific chemical afferents was well as visual cues contribute to food selection. Cav: normal=orthonasal olfaction of course contributes as well. It is, however, the retronasal component of olfaction that is relevant for the differentiation whether for instance exactly the same smell is related to sweaty feet or to a delicious cheese... Cave: Presumably there are no "special retronasal sensors" - crucial seems to be wehther the olfactory epithelium is stimulated by inhaled or expired air and whether the latter happens together with taste stimuli. In the perception of how food tastes and smells, there are three main players: the tongue, the retro-nasal cavity and the brain. Tastes picked up on sensors on tongue, transmitted via nerves to brain Aromas picked up by sensors in retro-nasal cavity and sent to brain
Labeled-line model
The different types of TRC are indicated by different colors as they can contain different types of receptor and intracellular modulator. The gustatory neurons with their associated colors that match the associated TRcs indicate that they respond best to those stimuli that activate the particular TRCs. These primary gustatory neurons project ipsilaterally to the rostral nucleus tractus solitarii (rNTS). The black colored axon that is embedded in the epithelia that surrounds the taste bud is likely to be a nociceptor. These neurons project ipsilaterally to the spinal nucleus of the trigeminal cranial nerve (SNV) and have collaterals that project to the rNTS.
Three functional components of the chemical senses
The sensory-discriminative component: The recognition of sweet, salty, bitter, etc. and how strong/weak the stimulus is. This involves the somato-sensory cortex. The affective component: Whether we like a particular taste/flavor - which is of course massively influenced by previous experience (learning), culture, et. This ilvolves the limbic system. The physiological "reflexive" component: The processing of chemosensory stimuli also triggers physiological reflexes (cephalic phase responses) from the secretion of digestive juices to endocrine or cardiovascular responses. This involves the hypothalamus.
Umami, sweet, bitter and sour tastes are coded by different receptors
The traces show recording of tastant-induced activity in nerves innervating the tongue in wild-type and various gene-knockout mice or cell ablation studies. T1R1+3 functions as the umami receptor, T1R2+3 is the sweet receptor, T2Rs are bitter receptors, PKD2L1 is the candidate sour receptor, and PLC-b2 is the effector and TRPM5 the transduction channel of sweet, umami and bitter pathways. Note the extraordinarily specific taste deficits (red traces) in each genetically altered mouse line. Pkd2l1-DTA refers to animals expressing diphtheria toxin in PKD2L1 cells.
Taste receptor cells < taste buds < taste papillae
There are about 3000-5000 Taste buds on the tongue. Half of them are located in the trenches atound the circumvallate papillae (only about 10) and one quarter each in the foliate papillae (15-20) and on the fungiform papillae (200-400), respectively. The fungiform papillae on the tip of the tongue contain only a few taste buds (<10). On the other hand, a circumvallate papilla in the back of the tongue may contain hundreds of them. The foliate papillae contain about 50 taste buds each. In addition, the tongue carries filiform papillae, which do not contribute to chemosensation. Rather, their horny tips register tactile stimuli. Unlike for olfaction, there is no adaptation for gustation, primarily because tiny glands in the papillae continuously rinse the receptors and, hence, rapidly remove the tastants.
Transmission of taste qualities
There are opposing vies of how taste qualities are encoded. a. The labelled line model surmises that TRCs are tuned to respond to single taste modalities and are innervated by individually tuned nerve fibers. In this case, each taste quality is specified by the activity of non-overlapping cells and fibers. b,c. Two variants of the "across-fiber pattern", stating that either individual TRCs are tunded to multiple taste qualities, and consequently the same afferent fiber carries information for more than one taste modality, or that TRCs are still tuned to single taste qualities but the same afferent fiber carries information for more than one taste modality. 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 fuctional studies in mice clearly favor the labelled line model.
Twenty-five structurally diverse bitter receptors (T2R)
What does this mean for bitter receptor cells? They express varying combinations of these 25 bitter receptors, i.e. they are tuned into detecting different subsets of bitter substances. T2R are widely expressed throughout the body and mediate diverse non-tasting roles through various specialized mechanisms. It has also become apparent that T2Rs and their polymorphisms are associated with human disorders.
ion channel receptors
sour PKD2L1 salt (Na+) ENaC Several cells, receptors and mechanisms have been proposed to encode sour taste. Genetic ablation and functional studies meanwhile demonstrated that a member of the TRP Ion-channel family, PKD2L1, mediates sour taste. PKD2L1 is selectively expressed in a population of TRCs distinct from those mediating sweet, umami and bitter tastes
