Molecular Genetics of Visual Transduction 
Charles S. Zuker, Ph.D. — Associate Investigator 
Dr. Zuker is also Associate Professor of Biology and of Neuroscience 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, a McKnight Scholar, and a Fellow of the 
Alfred P. Sloan Foundation. 
THE nervous system provides a dramatic exam- 
ple of the capabilities of cells to signal each 
other and to respond to environmental cues. An 
understanding of signal transduction mechanisms 
is essential for elucidating the cellular and molec- 
ular basis of information processing in biological 
systems. Phototransduction, the neuronal excita- 
tion process triggered by light and resulting in 
the generation of a receptor potential, provides 
an ideal model system in which to study signal 
transduction in response to an environmental 
stimulus. The aim of our research program is to 
elucidate mechanisms used for signal transduc- 
tion in the visual system, using a combined mo- 
lecular, genetic, and physiological approach. 
Drosophila is unique as an experimental organ- 
ism in that it allows a multidisciplinary approach 
to biological questions that will yield not only 
much new information, but may well provide a 
type of information not otherwise obtainable. 
First, the system is amenable to classical genetics: 
over the past decade several groups have isolated 
a large number of Drosophila mutants with spe- 
cific defects in behavior mediated by visual in- 
put. Many of these have been shown to define 
genes important for phototransduction. Second, 
since the eye is fully dispensable, it can be manip- 
ulated without affecting viability. Third, genes 
can be readily introduced into the Drosophila 
germline. Thus genes and the proteins they en- 
code can be experimentally manipulated in vitro 
and their functions studied in vivo in their nor- 
mal 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. Recently our efforts have focused on 
the characterization of genes encoding products 
involved in the intermediate events of the visual 
transduction cascade. 
An example of the power and utility of a ge- 
netic approach to identify molecules with unex- 
pected roles is the ninaA gene. ninaA mutants 
have a 10- to 20-fold reduction of rhodopsin lev- 
els. Characterization of the ninaA gene has 
shown that it encodes a visual system-specific 
polypeptide with high-amino acid sequence 
identity to the human cyclosporin A-binding 
protein, cyclophilin. Cyclosporin A is an immu- 
nosuppressing drug widely used to prevent graft 
rejection following transplant surgery. Cyclophi- 
lins are peptidyl-prolyl cis-trans isomerases that 
catalyze isomerization about the peptide bond be- 
tween a proline residue (Pro) and its amino 
neighbor (Xaa). A model for ninaA function is 
that opsin is a substrate for the ninaA protein; 
isomerization about one or several Xaa-Pro pep- 
tide bonds may be crucial for proper membrane 
intercalation, folding, or stability of opsins. 
In addition to ninaA, we are also studying pro- 
tein kinases and two arrestins involved in regu- 
lating this signaling process. We are using molec- 
ular, genetic, and physiological approaches to 
dissect the role of these proteins in vivo. The 
results of these studies should help us understand 
the molecular basis of sensory reception and in- 
formation processing and may help us understand 
abnormalities in the human visual and nervous 
systems. 
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