Molecular Genetics of Sensory Transduction 
Charles S. Zuker, Ph.D. — Associate Investigator 
Dr. Zuker is also Associate Professor of Biology and of Neurosciences at the University of California School 
of Medicine, San Diego. He received his Ph.D. degree from the Massachusetts Institute of Technology for 
studies with Harvey Lodish. He carried out postdoctoral research with Gerald Rubin in the Department of 
Biochemistry at the University of California, Berkeley, before joining the Department of Biology at UCSD. 
Dr. Zuker is currently a Pew Fellow in the Biomedical Sciences and a Fellow of the March of Dimes 
Foundation. 
AN understanding of signal transduction is es- 
sential to elucidating the cellular and molec- 
ular basis of information processing in biological 
systems. The primary event in the processing of 
visual stimuli is phototransduction, the conver- 
sion of light energy into a change in the ionic 
permeabilities of the photoreceptor cell mem- 
brane. The aim of our research is to clarify mecha- 
nisms used for signal transduction in the visual 
system, using a combined molecular, genetic, 
and physiological approach. The study of this pro- 
cess in Drosophila applies powerful molecular 
genetic techniques to identify novel transduc- 
tion molecules and to examine their function in 
vivo, in their normal cellular and organismal 
environment. 
Experimental Strategy 
Over the past few years my colleagues and I 
have been working on the isolation and character- 
ization of genes important for photoreceptor cell 
function. Most recently we have focused on genes 
encoding proteins involved in the regulation of 
the visual transduction cascade. We have identi- 
fied a protein kinase C (PKC) that is expressed 
exclusively in the Drosopbilavisual system. Anal- 
ysis of the light response from mutants defective 
in this PKC showed it to be required for the deac- 
tivation and rapid desensitization of the visual 
cascade. The availability of a PKC mutant in Dro 
sophila provides the basis for genetic and bio- 
chemical studies to identify biologically relevant 
substrates and regulators of this enzyme. 
Rhodopsin, like other G protein-coupled re- 
ceptors, is phosphorylated by a specific kinase 
upon activation (rhodopsin kinase). This reac- 
tion is thought to be involved in the termination 
of rhodopsin's active state. Phosphorylation, how- 
ever, is not sufficient for receptor inactivation, 
since the phosphorylated form can still activate 
the G protein. Complete inactivation has been 
shown {in vitro) to require the stoichiometric 
interaction of rhodopsin with a protein called 
arrestin, or S antigen. This protein has also been 
implicated in a number of autoimmune retinal 
disorders in mammals. We have isolated the 
genes encoding two photoreceptor cell-specific 
arrestin molecules in Drosophila and have gen- 
erated mutants of these genes. Our results should 
help us understand the molecular basis of G pro- 
tein-coupled receptor regulation and of relevant 
abnormalities in the human visual and nervous 
systems. 
Mechanotransduction 
We have recently begun to study mechano- 
transduction, the process by which specialized 
sensory cells convert mechanical stimuli — for 
instance, sound, touch, gravity, or movement — 
into electrical (neuronal) signals. In contrast to 
phototransduction, nothing is known about the 
molecular basis of mechanosensitivity. Our aim is 
to identify genes and proteins involved in mech- 
anotransduction by isolating mutations that affect 
mechanosensory behavior. 
When Drosophila larvae are touched gently, 
they contract and retreat. We have developed a 
screen for mutant larvae defective in this behav- 
ior and have isolated several mutant lines. Muta- 
tions that specifically affect the working of the 
sensory organs are of greatest interest. Mapping 
the mutations — in prelude to isolating and clon- 
ing the affected genes — is in progress. In addi- 
tion, we have developed a molecular approach to 
isolate genes expressed specifically in mechano- 
sensory organs. We are using developmental mu- 
tants that overproduce or lack mechanosensory 
bristles to isolate such genes by subtractive 
hybridization. 
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