Bad Aftertaste? New Sensory On/off Switch May 'Cure' Bane Of Artificial Sweetener Search

"This is not just an esthetic or parenting issue, but a majordietary and economic issue," according to Michael Naim, a professor atthe Hebrew University of Jerusalem. Naim pointed out that the foodindustry and individual cooks use such "tricks as masking the bittertaste of healthy greens with salad dressing or sugar, or in the case ofother foods, just taking out the offending taste. From the viewpoint ofnutrition 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 decadeshave developed numerous sugar substitutes, but most share a commonfailing: bad aftertaste. "Unfortunately for the industry and weconsumers," Naim said, "sucrose is regarded by humans as the optimalsweetener. In contrast to all the artificial sweeteners it has a puresweet taste, no aftertaste and no add-on attributes other thansweetness."

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, anduncovering even a hint of the physiology of "aftertaste" has been evenslower. But on the basis of recent experiments, Naim's team hasdeveloped a working hypothesis that certain bitter and artificial sweettastants somehow enter the taste-bud cells where they inhibit thenatural termination of the taste-receptor signal resulting in what wecall aftertaste.

The paper describing their work, "Inhibition of signaltermination-kinases by membrane-permeant bitter and sweet tastants:potential role in taste signal termination," appears in the Augustissue of the American Journal of Physiology-Cell Physiology, publishedby the American Physiological Society. Research is by MeiravZubare-Samuelov, Merav E. Shaul, Irena Peri, Alexander Aliluiko, OrenTirosh and Michael Naim at the Hebrew University of Jerusalem, Israel.

In their experiments, Naim's team found that oral stimulationof rats by certain bitter and artificial sweet taste molecules (orartificial sweeteners), are able to enter taste bud cells. Furthermore,they interfere with the natural shutoff switch in receptors when testedin isolated form in the test tube. Naim's team hypothesized that "byinhibiting the phosphorylation of the taste sensors, the receptorscontinue to be active, and so we continue to taste what is often anunwelcome sensation to begin with," Naim said. "Of course there may bemore than one mechanism at work and theoretically there are otherpossible approaches to this complex phenomenon," he concedes, "but sofar this hypothesis has held up to experimentation."

First breakthrough: identification of sweet and bitter receptors

In recent years, researchers have identified receptors for sweetand bitter tastes. These receptors belong to the family of G proteincoupled receptors (GPCRs) and are found on the plasma membrane of tastecells. In general, stimulation of this type of receptor leads tointracellular formation of such second messengers as IP3, cAMP, cGMP aswell as activation of some ionic channels.

"Termination of this signaling in most cases is initiated byreceptor phosphorylation, a kind of common physiological 'on/offswitch,'" Naim explained. In many cases, the activity of GPCRs isterminated due to phosphorylation by G protein coupled receptor kinases(GRKs) located in the cytosol (cell fluid) or in the cytosolic side ofthe plasma membrane. Inhibition of this phosphorylation delays signaltermination 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 andperhaps GRK2 and GRK6 are present in taste-bud cells," Naim reported."Furthermore, we show that the phosphorylation of rhodopsin, which weused as a model for GPCR, by GRK5, GRK2 was inhibited in vitro by avariety 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), anotherreceptor-related kinase, was also inhibited by these tastants.

On the basis of these findings, Naim's group "hypothesized thatsome non-sugar sweeteners and bitter tastants, in addition tostimulating taste GPCRs on the extracellular surface, permeate thecytosolic side to inhibit GRK (and perhaps other kinases), thusdelaying receptor phosphorylation and signal termination, and thereforemay 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.