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Bad Aftertaste? New Sensory On/Off Switch May ‘Cure’ Bane of Artificial Sweetener Search

August 29, 2005

BETHESDA, Md. (August 29, 2005) ““ It’s no secret that George Bush the Elder doesn’t like broccoli. That he’s not alone is no surprise. But the range of foods that many people won’t eat because they are sensitive to “bitter” taste, or, in the case of non-sugar sweeteners, an “unacceptable aftertaste,” is longer than you might think. These include spinach, lettuce and for some, even citrus fruits and juices.

“This is not just an esthetic or parenting issue, but a major dietary and economic issue,” according to Michael Naim, a professor at the Hebrew University of Jerusalem. Naim pointed out that the food industry and individual cooks use such “tricks as masking the bitter taste of healthy greens with salad dressing or sugar, or in the case of other foods, just taking out the offending taste. From the viewpoint of nutrition and health promotion, including removal of antioxidants, these are undesirable stopgap solutions.”

Responding to popular demands for lower-calorie foods, scientists together with the food industry over the past few decades have developed numerous sugar substitutes, but most share a common failing: bad aftertaste. “Unfortunately for the industry and we consumers,” Naim said, “sucrose is regarded by humans as the optimal sweetener. In contrast to all the artificial sweeteners it has a pure sweet taste, no aftertaste and no add-on attributes other than sweetness.”

A working ‘aftertaste’ hypothesis: certain tastants block the natural taste ‘off-switch’

Despite the obvious need for improved artificial sweeteners, progress in finding acceptable sugar substitutes is slow, and uncovering even a hint of the physiology of “aftertaste” has been even slower. But on the basis of recent experiments, Naim’s team has developed a working hypothesis that certain bitter and artificial sweet tastants somehow enter the taste-bud cells where they inhibit the natural termination of the taste-receptor signal resulting in what we call aftertaste.

The paper describing their work, “Inhibition of signal termination-kinases by membrane-permeant bitter and sweet tastants: potential role in taste signal termination,” appears in the August issue of the American Journal of Physiology-Cell Physiology, published by the American Physiological Society. Research is by Meirav Zubare-Samuelov, Merav E. Shaul, Irena Peri, Alexander Aliluiko, Oren Tirosh and Michael Naim at the Hebrew University of Jerusalem, Israel.

In their experiments, Naim’s team found that oral stimulation of rats by certain bitter and artificial sweet taste molecules (or artificial sweeteners), are able to enter taste bud cells. Furthermore, they interfere with the natural shutoff switch in receptors when tested in isolated form in the test tube. Naim’s team hypothesized that “by inhibiting the phosphorylation of the taste sensors, the receptors continue to be active, and so we continue to taste what is often an unwelcome sensation to begin with,” Naim said. “Of course there may be more than one mechanism at work and theoretically there are other possible approaches to this complex phenomenon,” he concedes, “but so far this hypothesis has held up to experimentation.”

First breakthrough: identification of sweet and bitter receptors

In recent years, researchers have identified receptors for sweet and bitter tastes. These receptors belong to the family of G protein coupled receptors (GPCRs) and are found on the plasma membrane of taste cells. In general, stimulation of this type of receptor leads to intracellular formation of such second messengers as IP3, cAMP, cGMP as well as activation of some ionic channels.

“Termination of this signaling in most cases is initiated by receptor phosphorylation, a kind of common physiological ‘on/off switch,’” Naim explained. In many cases, the activity of GPCRs is terminated due to phosphorylation by G protein coupled receptor kinases (GRKs) located in the cytosol (cell fluid) or in the cytosolic side of the plasma membrane. Inhibition of this phosphorylation delays signal termination in vision and some other systems.

GRKs found in taste cells, switch-off inhibited by nonsugar sweeteners, bitter tastants

“In experiments reported in this paper, we showed that GRK5 and perhaps GRK2 and GRK6 are present in taste-bud cells,” Naim reported. “Furthermore, we show that the phosphorylation of rhodopsin, which we used as a model for GPCR, by GRK5, GRK2 was inhibited in vitro by a variety of non-sugar sweeteners and bitter tastants.”

The tastants included: (artificial sweeteners) saccharin, NHD, cyclamate, D-tryptophan and acesulfame K, and (in the bitter spectrum) cyclo(Leu-Trp), caffeine, quinine, L-tryptophan, limonin and naringin. The phosphoryalization activity of protein kinase A (PKA), another receptor-related kinase, was also inhibited by these tastants.

On the basis of these findings, Naim’s group “hypothesized that some non-sugar sweeteners and bitter tastants, in addition to stimulating taste GPCRs on the extracellular surface, permeate the cytosolic side to inhibit GRK (and perhaps other kinases), thus delaying receptor phosphorylation and signal termination, and therefore may extend the taste response.”

Next steps and other theoretical considerations

Though the results to date seem quite positive, Naim warned that much remains to be proven.

- According to the paper: “Additional studies using the newly discovered taste GPCRs are needed to show their interaction with GRKs and possibly with other kinases, such as in intact cells in vivo, before anything can be unequivocally stated.”

- Furthermore, the “novelty of the proposed mechanism of signal termination may lie in the fact that the ligands themselves not only interact extracellularly with GPCRs to initiate the transduction chain, but may concomitantly interact intracellularly with downstream shutoff components to affect signal termination.”

- Also, the fact “that tastants inhibit PKA and not just GRKs suggests that they inhibit other kinases as well. Because these tastants are components of our daily diets and may access other tissues along the gastrointestinal tract, these results may have implications for cellular signaling in tissues other than those involved in taste.”

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