Mammals can detect sweet, bitter, sour, salty, and umami
(roughly speaking, amino acid) stimuli. The ability to
discriminate between such stimuli underlies our ability
to avoid noxious substances while recognizing sources
of high-caloric or nutrient-rich food. The Zuker lab is
currently interested in answering basic questions about
the detection of taste signals, focusing on the isolation
and characterization of genes encoding sweet, bitter,
and umami taste receptors. The process of identifying
proteins that may function as taste receptors proves a
powerful molecular tool to investigate not only the function
of taste receptor cells but also the logic of taste coding,
allowing us to ask questions such as: How is tastant specificity
and taste discrimination accomplished at the periphery?
What is the topographic organization of sweet, bitter,
and umami cells on the tongue? How is the information
transmitted and encoded in the afferent nerves?
In association with Nick Ryba at the NIDCR, Zuker's lab
has been carrying out a comprehensive molecular and genetic
dissection of taste transduction in mammalian model systems.
Initially, they isolated two novel families of taste receptors
expressed in subsets of taste receptor cells of the tongue
and palate. One of these, the T2Rs, encompasses ~30 different
genes that they feel encode mammalian bitter taste receptors.
The other family, the T1Rs, contains three members that
combine to function as the mammalian sweet (T1R2+3) and
amino acid (T1R1+3) taste receptors.
These discoveries suggest that the taste of bitter, sweet,
and umami may be transduced by "labeled lines"-separate,
independent pathways-in the periphery of the taste system.
Indeed, receptors for each quality appear, in Zuker's
hands, to be expressed in distinct populations of taste
cells. The entire family of bitter receptors get co-expressed
in all bitter-receptive taste cells, which are entirely
distinct from the taste cells expressing sweet or umami
receptors. Various imaging and electrophysiological experiments
have confirmed that cells containing one of these receptors
(or receptor families) respond only to ligands (i.e.,
taste compounds) with the appropriate overall taste quality.
An important question, however, arises when attempting
to connect these facts with the physiology of perception:
are the T2R receptors truly involved in faithfully transmitting
information about bitter tastes, and only bitter tastes?
Relatedly, are the other identified receptors specifically
related to transmission of information about sweet or
umami taste? The researchers in Zuker's lab have used
genetic engineering techniques to prepare mutant mice
that lack particular proteins-or particular parts of the
post- transduction cascade-and in so doing have provided
evidence in favor of this hypothesis. First, they prepared
mice lacking PL
2,
a phospholipase that lies downstream of the bitter, sweet,
and umami receptors. These mice proved to prefer all tastants
equally to water, suggesting that they are insensitive
to the specific qualities of sweet, bitter, and umami
tastes. They then produced new mutant mice in which PL2
function was rescued in subsets of cells expressing only
one or another receptor; the mice then preferred that
particular taste quality to the same degree as normal
mice (e.g., preferring sweet and rejecting bitter in a
concentration-dependent fashion). Importantly, the mutant
mice with a particular rescued receptor not only responded
normally to that particular tastant, but continued to
appear insensate to other tastes.
Most recently, Zuker and colleagues engineered mice
in which a non-taste receptor-a modified º-opioid receptor
that transduces a synthetic ligand never experienced by
normal mice-was expressed only in cells expressing T1R2,
sweet-responsive cells. These mice preferred the synthetic
ligand, which they normally ignore, similarly to other
sweeteners. This suggests that any chemical transduced
by cells expressing sweet receptors essentially tastes
sweet to the mice, further supporting the idea that sweet
is coded peripherally by a labeled line.
Future work in the Zuker lab will attempt to extend this
last result to bitter receptors, and to search for other
receptors-the receptor for sour, for instance. Recent
advances in molecular genetics will be used to extend
Zuker's analysis of taste coding to central processing
stations, as well. This bottom-up approach will allow
him to examine the degree to which the putative labeled-line
processing of taste stimuli can be extended into the central
nervous system.
