Charles S. Zuker
Professor of Biology, UCSD
Investigator, Howard Hughes Medical Institute
e-mail: czuker@ucsd.edu |
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MOLECULAR GENETICS OF SENSORY SIGNALING IN DROSOPHILA
The aim of our research program is to
elucidate mechanisms used for signal transduction in sensory systems.
In particular, we have focused on the molecular genetics of phototransduction,
mechanotransduction and taste transduction. Our long term goal
is to identify the molecular components of the underlying signaling
cascades so as to define how they interact and are regulated
to produce the final orchestrated response. The results obtained
from these studies should increase our understanding of the molecular
basis of sensory reception and information processing and will
be useful in understanding abnormalities in the human nervous
system.
PHOTOTRANSDUCTION
Phototransduction is an ideal model system
for the study of G protein-coupled signaling cascades. The study
of this signaling cascade in the fruit fly make it possible to
use powerful molecular genetic techniques to identify novel transduction
molecules, and then to examine the function of these molecules
in vivo, in their normal cellular and organismal environment.
Phototransduction in Drosophila
is a phosphoinositide-mediated, calcium-regulated signaling pathway.
Phosphoinositide-mediated signaling pathways are a very ubiquitous
and pervasive mode of intracellular transduction in eukaryotic
cells. Phosphoinositide second messengers can be found downstream
of many tyrosine kinase receptors and G protein-coupled seven
transmembrane receptors. Activation of phospholipase C (PLC) catalyzes
the hydrolysis of the minor membrane phospholipid PIP2 into the
second messengers IP3 and DAG. IP3 mobilizes internal stores of
calcium, which affect and modulate many cellular processes, and
DAG activates members of the protein kinase C family of proteins.
Our laboratory has been characterizing a number of molecules involved
in the activation and deactivation of the phototransduction cascade.
These include the light receptor molecule rhodopsin, G proteins,
PLC, enzymes involved in the synthesis of PIP2 and
breakdown of IP3, protein kinases required for modulating the
light response and the membrane channels responsible for generating
the receptor current.
MUTANTS INSENSITIVE TO THE BAT OF AN EYELASH
Mechanotransduction, the conversion of
mechanical stimuli into neuronal electrical signals, is the most
diverse and pervasive mode of sensory signal transduction. However,
little is known of the underlying molecular mechanisms. To identify
genes involved in mechanotransduction, Drosophila larvae
were screened for mutations affecting a behavioral response to
touch. Multiple mutations of this type were recovered in
several genes. Adult flies mutant in these genes showed behavioral
phenotypes ranging from reduced locomotor activity and mild ataxia
to total uncoordination. Extracellular recordings from mutant
mechanosensory bristles showed that mechanoreceptor potentials
were absent or reduced, while resting transepithelial potentials
were unaffected. A second genetic screen, for uncoordination,
yielded several additional mutant lines. These mutants now provide
the basis for a genetic, electrophysiological and molecular dissection
of mechanotransduction.
MOLECULAR GENETICS OF TASTE
Although much is known about the psychophysics
and physiology of taste, little is known about the different molecular
components involved in mediating the four basic taste modalities
(sweet, sour, bitter and salty).
Genetic approaches seem ideally suited
to the task of identifying and isolating molecules involved in
taste transduction. The isolation of genetic mutations does not
depend on any assumptions about the nature of the target molecules,
other than that their function results in a recognizable phenotype.
Furthermore, the mutability of a gene is independent of both its
expression profile and the abundance of its product. Using simple
behavioral screens, like food choice discrimination combined with
food coloring dyes, our lab recently began a large-scale genetic
screen for mutants defective in taste transduction. It is expected
that the genes defined by those mutations will provide important
insight into the biology of taste.
Scott, K., Y. Sun, K. Beckingham
and C.S. Zuker (1997). Calmodulin regulation of Drosophila
light-activated channels and receptor function mediates termination
of the light response in vivo. Cell 91: 375-383.
Scott, K., and C.S. Zuker (1998).
Assembly of the Drosophila phototransduction cascade into
a signalling complex shapes elementary responses. Nature 395:
805-808.
Hoon, M.A., E. Adler, J. Lindemeier,
J.F. Battey, N.J.P. Ryba and C.S. Zuker (1999). Putative mammalian
taste receptors: a class of taste-specific GPCRs with distinct topographic
selectivity. Cell 96: 541-551.
Walker, R.G., A.T. Willingham, C.
Zuker (2000). A Drosophila mechanosensory transduction channel.
Science, 287: 2229-2234.
Adler, E., M.A. Hoon, K.L. Mueller,
J.Chandrashekar, N.J.P. Ryba and C.Zuker (2000). A novel family
of mammalian taste receptors. Cell 100: 693-702.
Chandrashekar, J., K.L. Mueller,
M.A. Hoon, E. Adler, L. Feng, W. Guo, C.S. Zuker and N.J.P. Ryba
(2000). T2Rs function as bitter taste receptors. Cell 100:
703-711.
Nelson, G., M.A. Hoon, J. Chandrashekar,
Y. Zhang, N.J.P. Ryba, C.Zuker (2001). Mammalian sweet taste receptors.
Cell, 106: 381-390.
Nelson, G, J. Chandrashekar, M.A.
Hoon, L. Feng, G. Zhao, N.J. Ryba and C.S. Zuker (2002). An amino-acid
taste receptor. Nature, 416: 199-202.
Zhang, Y., M.A. Hoon, J. Chandrashekar,
K.L. Mueller, B. Cook, D. Wu, C. Zuker and N.J. Ryba (2003). Coding
of sweet, bitter and umami tastes: Different receptor cells sharing
similar signaling pathways. Cell, 112: 293-301.
Zhao, G.Q., Y. Zhang, M.A. Hoon,
J. Chandrashekar, I. Erlenbach, N.J.P. Ryba, C.S. Zuker (2003).
The Receptors for Mammalian Sweet and Umami Taste. Cell, 115:
255-266.
Avidor-Reiss, T., A.M. Maer, E. Koundakjian, A. Polyanovsky, T. Keil, S. Subramaniam and C.S. Zuker (2004). Decoding cilia function: defining specialized genes required for compartmentalized cilia biogenesis. Cell 117: 527-539.
Mueller, K.L., M.A. Hoon, I. Erlenbach, J. Chandrashekar, C.S. Zuker and N.J.P. Ryba (2005). The receptors and coding logic for bitter taste. Nature 434: 225-229.
Huang, A.L., X. Chen, M.A. Hoon, J. Chandrashekar, W. Guo, D. Tränkner, N.J.P. Ryba and C.S. Zuker (2006). The cells and logic for mammalian sour taste detection. Nature 442: 934-938.
Zelhof, A.C., R.W. Hardy, A. Becker and C.S. Zuker (2006). Transforming the architecture of compound eyes. Nature 443: 696-699.
Chandrashekar, J, M.A. Hoon, N.J.P. Ryba and C.S. Zuker (2006). The receptors and cells for mammalian taste. Nature 444: 288-294.
Charles Zuker received his Ph.D. from MIT. He was a Jane
Coffin Childs Fellow in the Department of Biochemistry at UC Berkeley.
