Bitter Taste Signaling
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Bitter Taste Signaling
The sense of taste plays a critical role in the life and nutritional status of humans and other organisms. Human taste perception may be categorized according to four well known and widely accepted descriptors, sweet, bitter, salty, and sour (corresponding to particular taste qualities or modalities), and two more controversial qualities: fat and amino acid taste. In addition to these basic tastes, the taste buds also detect a meat-like taste known as umami in protein-rich food. The food chemicals that produce tastes set off different reactions from the taste buds with a main goal of sending signals along nerve fibers to the brain for interpretation. The perception of bitter taste is essential for its protective value, enabling humans to avoid potentially deadly plant alkaloids and other environmental toxins (Ref.1). On the tongue, the taste buds are mounted in special folds and protrusions called papillae. In humans, there are three types of sensory papillae. The fungiform papillae are located on the most anterior part of the tongue and generally contain one to several taste buds per papilla. The foliate papillae (15-30) are situated on the edge of the tongue slightly anterior of the circumvallate line. They are predominantly sensitive to sour tastes. The circumvallate papillae (7-15) are situated on the circumvallate line and confer sour/bitter sensitivity to the posterior two-thirds of the tongue. In total, an adult human may have several thousand taste buds.

The taste buds are specialized "onion-shaped" structures that are distributed throughout the oral cavity and comprise 50-100 individual TRCs (Taste Receptor Cells) whose apical and basal sides are separated by cation-selective tight junctions, so called because they are permeable only to small cations and anions. Because of their moderate cation selectivity, tight junctions can influence the taste of salts and acids. The restricted diffusion of anions provides a rational explanation of why NaCl tastes different from sodium gluconate and why citric acid tastes different from HCl. Taste sensation is realized in the mouth when the chemicals in food are dissolved by saliva. The free floating molecules are then able to enter a taste bud through the pore at its center. The taste bud is activated by different mechanisms depending on the type of taste, which then activates the appropriate cranial nerves. The sensations of bitter and sweet tastes are initiated by the interaction of sapid molecules, "tastants" with GPCR (G-Protein-Coupled Receptors) in the apical membranes of TRCs. The apical surface of TRCs, which makes contact with the oral cavity, is rich in convoluted microvilli containing GPCRs, ion channels, and other transduction elements (Ref.2 & 3). These proteins serve as receptors for sensory qualities such as salty, sour, sweet, umami and bitter taste, and trigger the downstream transduction events within taste cells. Included among these events is the firing of action potentials, which taste cells, like neurons, are able to generate by means of voltage-gated Na+, K+ and Ca2+ channels.

Bitter taste is unpleasant though bearable when weak, but repulsive when strong. Many organic molecules, originating from plants and interfering with the internal signaling system of animals and humans, are bitter, including caffeine, theophylline, nicotine, quinine, strichnine, cycloheximide, denatonium, PROP (6-n-propyl-2-thiouracil), and many drugs produced by industry. Bitter taste effectively warns us not to ingest potentially harmful compounds. 24 GPCRs of the T2R family respond to bitter agents. Members of the T2R family are co-expressed with the Alpha-subunit of the G-Protein Gustducin, a taste-specific signaling protein long known to have a prominent role in bitter taste. The subunits of Gustducin (identified as G-Beta3 and G-Gamma13) are activated by specific bitter-stimulated T2R/TRB receptorsthat mediate two responses in TRCs: a decrease in cNMPs (Cyclic Nucleoside Monophosphates, cAMP or cGMP) via G-Alpha Gustducin (GNAT3) and a rise in ACs (Adenylate Cyclase), IP3 (Inositol1, 4, 5-Trisphosphate)/DAG (Diacylglycerol) via G-Beta3 and G-Gamma13. Although a variety of mechanisms have been proposed for taste transduction, all three modalities (sweet, salt and bitter) use elements of a common pathway; receptors signal through a heterotrimeric G-Protein to PLC-Beta2 (Phospholipase-C-Beta2), which breaks down PIP2 (Phosphatidylinositol 4,5-Bisphosphate) into IP3 and DAG, and IP3 opens Ca2+-release channels to elevate intracellular Ca2+ (Ref.4). The subsequent steps in the Alpha-Gustducin-PDE (Phosphodiesterase)-cNMP pathway are presently uncertain. Decreased cNMPs act on protein kinases, which in turn regulate TRC ion channel activity, or cNMP levels may directly regulate the activity of cNMP-gated and cNMP-inhibited ion channels expressed in TRCs. The subsequent steps include the activation of IP3R (IP3 Receptors) and release of Ca2+ from internal stores followed by neurotransmitter release. Some bitter peptides with amphophilic properties also interact directly with G-Proteins, by virtue of a structural similarity to the G-protein-binding site of the receptor. Quinine, also an amphophilic compound, permeates the cell membrane and activates G-Proteins, bypassing the receptor. Denatonium blocks voltage-gated delayed-rectifier KCn (K+ Channels). Caffeine and other methyl-xanthines also act without activating a GPCR. After permeating the cell membrane they block an intracellular PDE and cause activation of a soluble GC (Guanylate Cyclase). The latter effect may be under control of NO (Nitric Oxide), as NOS (Nitric Oxide Synthase) is found in taste cells. As a result of these complex events there is a transient increase in cGMP (cyclic Guanidine 3, 5- Monophosphate) (Ref. 4 & 5).

Taste is an essential sensory system devoted primarily to check the quality of food being ingested. Although aided by smell and visual inspection, the final recognition and selection relies on chemoreceptive events in the mouth. Taste drives appetite and protects us from poisons. So, we like the taste of sugar because we have an absolute requirement for carbohydrates (sugars etc.). We get cravings for salt because we must have sodium chloride (common salt) in our diet. Bitter and sour cause aversive, avoidance reactions because most poisons are bitter and off food go sour (acidic) (Ref.6).