October 31, 2003
Researchers Define Molecular Basis of Human "Sweet Tooth" and Umami Taste
Halloween turns millions of kids into candy-loving monsters with
more than ample supply of confections to satisfy their “sweet
tooth.” Now, Howard Hughes Medical Institute researchers have
moved closer to understanding why some people cannot resist the
impulses brought on by sweets.
The researchers created mice with the same sweet-tooth preferences
as humans by inserting the gene that codes for a human sweet-taste
receptor protein into the animals. They also inserted an entirely
different receptor gene into the taste cells of mice, thereby producing
animals that perceive a previously tasteless molecule as sweet.
“Our own sweet preferences are likely to be not simply an issue of cultural differences, as some have argued, but to be genetically encoded.”
Charles S. Zuker
Both of these experiments demonstrate that receptor molecules on the
tongue for both the sweet and “savory” umami tastes are
what triggers taste cells on the tongue and palate to transmit taste
signals to the brain. Umami taste responds to amino acids such as
monosodium glutamate.
The researchers said their findings open the way for tracing the
circuitry for sweet and umami tastes all the way to the centers in the
brain that perceive those tastes. The findings also suggest that
individual variations in the “sweet tooth” response may lie
in subtle genetic differences in receptor molecules that perceive sweet
taste.
The findings were reported in the October 31, 2003, issue of the
journal Cell by a research team led by Howard Hughes Medical
Institute investigator Charles
Zuker at the University of California, San Diego, and Nicholas Ryba
of the National Institute of Dental and Craniofacial Research.
“In our previous work, we reported that we had found the best
candidate sweet and umami receptor molecules,” said Zuker.
“But there remained two major outstanding questions. First, do
these receptors function in vivo as taste detectors? And
second, are they members of a larger group of such receptors, or are
they the receptors for sweet and umami taste? These
experiments have conclusively answered both questions; sweet and umami
taste are mediated entirely by these receptors.”
The candidate receptors that Zuker, Ryba and their colleagues
identified are complex proteins on the surfaces of taste cells. When
stimulated, these proteins switch on internal cellular machinery, which
begins the process of sending a signal about the taste to the brain.
The umami receptor is a combination of two protein subunits called T1R1
and T1R3. Sweet, on the other hand, is mediated by two different
receptors: a combination of T1R2 and T1R3, which responds to natural
and artificial sweeteners, and T1R3 which responds only to high
concentrations of sugars.
In their experiments, Grace Zhao and colleagues first produced
knockout mice lacking each one of the three types of subunits. To test
the response of the knockout mice to sweet or umami tastes, they
measured the behavioral preference of the mice for either plain or
flavored water. They also measured the direct response of the taste
cells to sweet- or umami-tasting chemicals by performing physiological
studies on the nerves that carry taste information.
Their studies showed that mice lacking either the T1R1 or T1R3
subunits lost all response to umami tastes. And knockout mice lacking
either T1R2 or T1R3 lost preference for almost all sweet tastes.
However, those mice retained some ability to respond to high
concentrations of natural sugars, suggesting that either of the
subunits could function on its own as a “low-affinity”
sweet receptor. When the scientists produced double-knockout mice
lacking both components of the sweet receptors, those animals lost all
response to sweet-tasting chemicals.
Additional cell-based studies revealed that the T1R3 protein alone
responds to high concentrations of natural sugars, but not to lower
concentrations, or to artificial sweeteners. “This finding may
explain why artificial sweeteners never attain the level of sweetness
that natural sugars do,” said Zuker. “Artificial sweeteners
activate only the T1R2+T1R3 combination of subunits in the sweet
receptor, while natural sugars also activate T1R3 alone.”
One puzzle about sweet taste is why humans can taste a number of
natural and artificial sweeteners that rodents cannot. These include
the intensely sweet (to humans) proteins monellin and thaumatin found
in certain fruits, and the artificial sweetener aspartame.
To demonstrate that the human “sweet-tooth” preferences
lie in the receptors, the researchers generated mice with the human
T1R2 receptor, which is significantly different in sequence from the
mouse counterpart. “We found that these mice with the human
receptors like the same sweet molecules that we humans do,” said
Zuker. “They loved both the sweet proteins and the aspartame
flavor.
“This proves that the species differences are a reflection of
the sequence of the receptors, and strongly suggests that our own sweet
preferences are likely to be not simply an issue of cultural
differences, as some have argued, but to be genetically encoded.”
For example, slight genetic differences in receptor proteins
“might explain why one person needs five spoons of sugar in his
coffee and another needs only two — because the first person's sweet
receptors need more sugar to get the same kick.”
To demonstrate conclusively that the responses of the taste cells
themselves are what determine taste perception, Zhao and her colleagues
performed an even more radical genetic replacement. They introduced
into the sweet-tasting cells of mice a receptor for an entirely
unrelated, synthetic opioid compound.
When the mice were presented with the compound, “much to our
delight, these mice were strongly attracted to this novel
chemical,” said Zuker. “They thought it was sweet, even
though we humans (or even the very same mice prior to expressing the
gene) would find it tasteless.”
The ability to genetically manipulate taste cells in such a way
gives researchers a major entrée into the taste centers of the
brain. “Now we can follow the connectivity from the tongue all
the way to the brain and begin to define what cells in the brain are
responsible for behavioral responses to each of these taste
modalities,” he said. By inserting foreign receptors into taste
cells, said Zuker, researchers can be assured that they are tracking
the behavior of just that taste circuit and not others that might be
triggered by the same receptor — in essence “a labeled
line.”
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