Taste perception is important as nutrients often contain toxic substances which are associated with a bitter taste perception. Two taste receptor families (TAS1R and TAS2R) are responsible for a sweet, umami and bitter taste perception. The taste perception might also be influenced by different taste receptor polymorfismen. However, in order to find out whether this is the case more research has to be done.
It should be noted that TAS1R and TAS2R are structurally different. As a result TAS1R might be able to dimerize by interaction of two lobes which form a clamshell together, whereas TAS2R might not.
Human beings are able to taste different flavors (sweet, salt, sour, bitter and umami) because of taste buds in the tongue. A taste bud contains all taste receptors. Tasting different flavors is place independent in the tongue. The "taste receptors" (salt and sour) are activated by compounds (ligands) in food, which bind to the taste receptors. By stimulating the receptors, electrical signals are send via nerve fibers to the cell membrane. The electrical charges on the cell membrane will change. The latter results in an action potential.
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Compensation of differences in the electrical charges are achieved by opening ion channels. Sodium ions will go into the cell, which depolarize the cell and thereby release neurotransmitters. These neurotransmitters will bind to nerve cells which will send the taste signal to the brain.
Figure 1: Schematically overview of Taste receptor functionTaste receptors for a sweet or bitter taste have another mechanism though. G-protein-coupled receptors are involved in the signal transduction. G-protein-coupled receptors comprise a protein family of transmembrane receptors. These receptors consist of an extracellular, transmembrane and intracellular domain. Ligands bind to the extracellular domain of the g-protein-coupled receptor, which activates intracellular signaling pathways. This will infinitely result in a cellular response, like taste perception.
There are, as was stated in the introduction, two different taste receptors families in humans, namely: T1R and T2R. T1R is a receptor family for a sweet or umami taste perception, whereas T2R is involved in tasting bitter. Each taste receptor family consists of several polymorfismen, which makes the understanding of the taste perception mechanism more difficult.
Polymorfismen are DNA variations caused by errors arising during DNA replication. The polymorfismen are responsible for the gen variations in the taste receptors. These gen variations might change the eating behavior of individuals. This can be investigated by using 6-n-propylthiouracil (PROP) as a marker.
1.1 Taste system development and signaling information
The biological definition of taste is defined as sensations, which are mediated by a specialized anatomically and physiologically defined chemosensory gustatory system  .
All vertebrates have a functional taste system when they are born. This sensory system is important for animals to survive, for example in recognizing lethal substances in their food. During embryogenesis, the four basic elements of the taste system must connect accurately:
(1) Taste buds in the mouth and pharynx; (2) sensory neurons in the cranial nerve ganglia, which connect taste buds to (3) the hindbrain, which is connected to (4) nuclei in the brain  .
Taste buds are located in taste receptor cells from the gustatory system. Most of the taste buds are located in the tongue and belong to three types: foliate, vallate and fungiform.
Taste stimuli (for example water-soluble chemicals) interact with the apical ends of the taste receptor cells in the oral cavity. The binding of taste stimuli is responsible for the taste perception, which is generated by signals, which are transmitted to the brain via nerves.
Most of the taste stimuli cannot easily permeate the cell membrane and thereby bind to taste GPRC's. There are ligands though, like for example sodium and some bitter compounds which can penetrate the cell membrane. These particularly compounds might interact with intracellular targets to active taste receptors.
Taste perception is important as nutrients often contain toxic substances, which are associated with a bitter taste.ÂÂ
2. Tas1R and Tas2R, the taste receptor families
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2.1 Taste receptor family, Tas1R
2.1.1 Discovery of Tas1R
The T1R receptor family has been discovered by means of two similar studies. The first study started to investigate genetic locus control of saccharin preference in mice. From this study it became clear that the preference of mice for saccharin involving free choice seems to be regulated by a single locus called Sac  . Two loci on chromosome 4, the Sac locus and dpa locus, were responsible for more then 50% of the genetic variability in sucrose intake and influenced the afferent responses of gustatory nerves to sweet compounds. This indicated that the Sac locus is involved in peripheral neural responses, which suggested (in 1997) that the Sac gene might encode a sweet taste receptor  .
However, another study rejected the latter assumption, in which became clear that Tas1r1 and Sac showed distinct locations.
The most important discovery came from positional cloning study in 2001. By genetic and physical mapping a genomic interval was limited to a 194kb DNA fragment. The DNA fragment could be sequenced and this identified the Tas1r3 gene, a member of the T1R family  .
2.1.2 Tas1R structure and ligand binding
Tas1R taste receptors can be divided in two groups: sweet (Tas1R2 + Tas1R3) and umami (Tas1R1 + Tas1R3) taste perception. Both groups belong to the C family GPCRs by their homology and sequence. This GPCR family is characterized by a typical 7-transmembrane helix and large extracellular domain (functioning as a orthosteric ligand binding domain). It is also known that family C GPCRs dimerize along their TM and extracellular domains. This is in contrast with most GPCRs, which dimerize along their TM domains.
The heptahelical domain (HD) is insignificant to the sequence of other GPCR's. There are however a few conserved residues in rhodopsin-like receptors which are conserved in family C GPCR's too. This suggests that these GPCR families might originate from a common ancestral gene.
Figure 2: Schematic representation of a family C GPCR. These receptors are characterized by a N-terminal extracellular VFTM (850 amino acids), which is interconnected to a HD via a CRD and terminated by a variable C-terminal intracellular tail.
extraextracellular VFTMFamily C receptors are activated by ligand binding within the VFTM, which is then transmitted to the TM domain and finally by cytoplasmic loops to the G-protein.
The sweet taste receptors has multiple binding sites for sugars and artificial sweet tasting compounds  . These binding sites might change because of gen variations within the taste receptors.
T1R ligand binding has been examined in two types of studies (ligand overview: attachment table 1). In the first study responses to taste stimuli in T1R transfected cells were analyzed by in vitro hetrologous expression experiments. The other study involved in vivo experiments, which examined taste responses in mice due to the effects of Tas1r genotypes.
Other experiments were set up as well to characterize the functional importance of the domains of T1R. These studies involved amongst others heterologous expression of various T1R polymorfismen from different species  .
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The conformational change which takes places upon ligand binding is expected to be transmitted from the VFTM and CRD to the transmembrane domain, where it activates the G-protein at the cytoplasmic surface.
2.1.3 T1R gene variation and taste perception
To investigate the influence of T1R gene variation on taste perception, various studies in humans, rats and mice have been performed.Species variation in humans and strain variation in rats and mice has been taken into account.
Taste ligands are likely to bind to the N-terminus extracellular domain. This is were the majority of amino acid sequence variation occurs. From these studies it became clear as well that polymorfism TAS1R2 was particularly diverse compared to other human genes. Henceforth it was predicted that the variation in TAS1R contributes more to variation in sweet taste perception (depends on variation in TAS1R2 and TAS1R3) then umami taste perception (depends on variation in TAS1R1 and TAS1R3)  .
These experiments were insufficient though to establish the genetic determination of variations in taste receptor genes due to the fact that perception and preferences of sweet are affected by a range of variables like genetics, age, cultural believes and personal experiences  . As a result of these finding and knowledge an important question might be: which influence is stronger, the genetic preference for sweet or one's cultural believes and personal experiences? Each individual has its own personal experiences and cultural believes. So, why should this aspect been taken into account by doing these experiments? Are the investigators still looking for the genetic influences only or is it a mixture of different variables.
2.2 Taste receptor family, Tas2R
2.1.1 Discovery of Tas2R
I. Lush is a geneticist who predicted the existence of bitter taste receptors in 1995. He has been studying mouse strain differences in bitter taste perception and suggested the bitter and sweet tasting genes have evolved from a common ancestor. He suggested as well that this was caused by a process of differentiation and local duplication and that this evolution took place before the tetraploidization of the genome  .
Adler et al. and Matsunami et al. discovered the T2R genes in 2000. This new discovery was based on released human genome sequences, which were associated with genome regions of bitter taste perception in humans and mice.
Adler et al. was the first to discover a novel rodent GPCR, TAS2R1, which was expressed in a subset of taste receptor cells of the tongue. They examined a region of human chromosome 5 and showed that these T2Rs responds to 6-n-propyl-2-thioracil (PROP), which is often used as a marker for individual taste perception.
Matsunami et al. revealed related genes of TAS2R in human chromosome 7 and 12, by doing similarity searches. This group also found conserved syntheny of human chromosome 12 to mouse chromosome 6 containing the Soa (sucrose octaacetate aversion) locus, a bitter tasting gene. Several groups have identified other TAS2R genes. One of them is Conte et al. who revealed new TAS2R genes by starting an informatics homology based screen of human genome draft for sequences related to the TAS2R family of taste receptors. They first collected all TAS2R sequence information from public databases and the GeneSeq database (patented sequences): 50 entries of human TAS2R related sequences were discovered. "Two of those entries shared 98% identity, 20 were partial sequences, 12 contained at least one frameshift or a premature stop codon and 17 appeared to be full-length TAS2R genes". They then aligned all publicly available TAS2R receptor sequences and developed an HMM model characteristic of the TAS2R family to search in a database of protein translations of predicted human genes and in ORFs predicted in unannotated high-throughput genomic se- quences (HTGS). Sequences with more than 98 % nucleotide or amino acid identity were seen as identical. Sequences containing one or more disruptions in a ORF were considered as pseudogenes. From this experiment 11 human TAS2R genes (TAS2R51 to TAS2R61) and four pseudogenes (TAS2R62 to TAS2R65) were identified. These experimental findings were validated by PCR amplification of human genomic DNA.
2.2.2 Tas2R structure and ligand binding
Tas2R taste receptors are bitter-taste GPCR receptors. A bitter taste is normally seen as a warning for the human body and is associated with poisonous substances. 6-n-propylthiouracil (PROP) is a bitter-tasting compound and is used as a marker for individual taste perception. Insensitivity to PROP can arise from gen variations in the Tas2R38 gene  .
The coding region of Tas2R, like many other GPCRs consists of exons only and is fold into a TM, intracellular and extracellular domain  ,  ,  ,  ,  . This seems quite similar to other GPCRs, but these bitter taste receptors lack sequence relationships to other GPCRs and many other characteristics of typical GPCRs.
Mutations in Tas2 receptors are likely to occur in the extracellular parts, because the extracellular domains are less conserved than the transmembrane and intercellular domains.
Humans perceive many compounds as bitter, and this number is much larger than the number of TAS2R genes. This implies every TAS2R responds to more than one structurally diverse bitter compound. Failure in detecting such compounds, like strychnine, a natural occurring bitter compound might be fatal and is therefore very important  .
Figure 3: Schematic representation of TAS2R structure. Characterized by a seven TMD and a short extracellular N-terminus (300-330 amino acids).
It is remarkable that some of the TAS2Rs interact with a wide range of ligands, while some other T2Rs appear to have narrow ligand specificities. An overview of the ligands, which are detected for humans, rats, chimpanzees and mice can be seen in table 2.
In vitro and in vivo studies have been carried out to investigate T2R ligand specificity. Most of these studies were in vitro based though.
2.2.3 T2R gene variation and taste perception
TAS2R genes are responsible for a bitter taste perception and diversity in the coding sequence of these genes is known. This diversity can be responsible for differences in personal bitter taste perception. A relationship between taste perception and TAS2R genes has only been demonstrated for TAS2R38. This relationship might arise by variation in receptor function, which can alter the perceived qualities of food and thereby change nutrition intake. TAS2R38 is located on chromosome 7 and taste perception of this gene can be investigated by using PROP and PTC (PTC is also known as phenylthiocarbamide and phenylthiourea, which is an organic compound that normally tastes bitter. However a difference in genetic makeup might change the perception of this compound and therefore it tastes tasteless).
Allelic variants of TAS2R38 on chromosome 7q have shown a strong linkage between PTC perception and single nucleotide polymorphism. Three coding SNP gave rise to five haplotypes in this gene. These haplotypes completely explain the bimodal distribution of PTC taste sensitivity, thus accounting for the inheritance of the classically defined taste insensitivity and for 55 to 85% of the variance in PTC sensitivity. Distinct phenotypes were associated with specific haplotypes, which demonstrate that this gene has a direct influence on PTC taste sensitivity and that sequence variants at different sites interact with each other within the encoded gene product  .
2.2.4 Racial differences and TAS2R taste perception
Eating behavior is dependent on race. For example Japanese people eat raw fish, whereas most people from the Netherlands do not. This difference might come from eating habits taught from birth, but it might also come from taste gene polymorphism.
Figure 4: Distribution of sharing of SNPs across the investigated populations. The Y-axis represents the number of SNPs observed in the different populations. The breadth of distribution of the SNPs in categorized by a color, with different colors indicating the number of populations in which they are variable. The gray portion of each bar indicates the number of SNPs unique to that population, and the light blue portion indicates the number that are found in all populations tested. Population codes: Cameroonians (CAM); Amerindians (AME); Japanese (JAP); Hungarians (HUN); Pygmies (PYG)24 human TAS2R genes were sequences to identify the racial differences of African, Asian, European and North American people by looking at single nucleotide polymorphisms. The researches found a high degree of nucleotide variation (ranging from 1 SNP in TAS2R13 to 12 SNPs in TAS2R48). It was also discovered the Cameroonian population had the greatest number of alleles (the African population had also a great number of alleles, which was investigated in another study though  ). 
2.3 Dimerization of taste receptors
Dimerization is a well-known aspect for activation of tyrosine kinase receptors. This dimerization results from binding of a signal molecule to the extracellular domain of a tyrosine kinase receptor, causing two receptor molecules to dimerize. The signaling molecule is a dimer and can therefore cross-link two receptor molecules, which activate the tyrosine kinase receptor.
GPCRs were classically assumed to be function as a monomer and the signal transduction was based on this assumption. Nowadays it has been proved GPCRs can also form homodimers and heterodimers  .
Figure 5: Schematically representation of mGluR1 dimerization through two lobes 1 (LB1) of each monomermGluR1, a family C receptor, showed disulphide linked homodimers from which the active/resting conformation is modulated by the dimeric interface  . This receptor is also characterized by a N-terminal extracellular VFTM, like every other family C receptor. The VFTM region is important, because each VFTM monomer has two lobes that together form a clamshell. The dimerization between the monomers is caused by interaction of two lobes 1, the two lobes 2 are not involved in the dimerization (figure 5).
The crystal structure of mGluR1 matches the predicted secondary structures of helices and ß strands of the extracellular domain of TAS1R at almost every point.
Figure 6: Schematically picture of the orthosteric and allosteric binding sites of Family C dimerized GPCRsFrom this information it is expected that TAS1R dimerizes and binds ligands in a similar way as mGluR1 does.
Finally, some other studies have revealed the separation between orthosteric and allosteric binding sites for family C GPRCs (figure 6)  . It also became clear that allosteric binding of a ligand to one monomer can modulate the binding and function of the orthosteric ligand of the other monomer via cooperative binding  . An overview of some allosteric family C GPCR ligands can be found in attachment, figure 7.
Dimerization of TAS1R depends on the existence of a N-terminal extracellular VFTM. TAS2R is missing this extracellular domain and is thereby probably not dimerized.
Table 1: Overview of T1R ligands
Table 2: Overview of T2R ligands
Figure 7: overview of some allosteric family C GPCR ligands