SIGNAL TRANSDUCTION AND NEUROGENESIS IN THE OLFACTORY SYSTEM 
Randall R. Reed, Ph.D., Associate Investigator 
The mammalian olfactory system is an exquisitely 
sensitive sensory organ responsible for encoding in- 
formation on the intensity and the identity of chem- 
ical stimuli. The receptor neurons responsible for 
this initial step in olfactory signal transduction are 
unique in their capacity to be replaced continually 
from a population of neuroblast-like precursors 
throughout adult life. Dr. Reed is investigating two 
central problems in neurobiology: How do neurons 
transduce a complex external stimulus into an elec- 
trical signal? What are the molecular processes that 
accompany neural development? 
The initial events in olfactory signal transduction 
occur in a complex sensory organ, the nose. Mole- 
cules that comprise the chemical stimulus we per- 
ceive as odor are first solubilized and concentrated 
by protein components of the aqueous medium 
that bathes the tissue. The neuroepithelium that 
lines the nasal cavity contains the sensory neurons 
responsible for the conversion of the external stim- 
ulus into an electrical signal. Each of these sensory 
neurons extends a dendritic process to the luminal 
surface, where a small number of cilia extend into 
the mucous layer. These cilia, the presumed site of 
odorant recognition, likely contain the machinery 
required for signal transduction. Axons extend from 
the cell bodies located in the epithelium to glomer- 
ular tufts in the olfactory bulb. 
The replacement of olfactory neurons from neu- 
roblast precursors occurs continually in adult ani- 
mals. Acute injury to the olfactory bulb or the re- 
ceptor neurons leads to the rapid loss of these 
sensory cells and their subsequent, synchronous re- 
placement. 
I. The Mechanism of Olfactory Signal Transduction: 
A G Protein-Coupled Cascade. 
Receptor proteins present in the cilia membranes 
of the sensory neuron are presumed to provide the 
specificity of odorant recognition. These receptor 
proteins might then converge on a common intra- 
cellular pathway. Recently, Dr. Reed has identified 
several components in the presumptive pathway 
for olfaction. The laboratory has characterized a 
GTP-binding protein, G^^^ exclusively expressed in 
the olfactory neurons and localized to the sensory 
cilia. This olfactory-specific G protein shares some 
homology to transducin, the G protein involved in 
visual signal transduction. 
The cyc~ variant of the 549 mouse lymphoma cell 
line is deficient in GTP-stimulated adenylate cyclase 
activity and has proven to be a useful system to in- 
vestigate G protein function. When G^,j is intro- 
duced into this cell line, GTP-dependent adenylyl 
cyclase activity is restored. Moreover the ability of a 
P-adrenergic agonist, isoproterenol, to stimulate ad- 
enylyl cyclase is also restored. These data suggest 
that G^ij can couple heterologous receptors to ad- 
enylyl cyclase and provide some insight into the 
similarity of olfactory receptors to other known G 
protein-coupled receptors. The membrane-bound 
receptors that couple to G proteins share consider- 
able structural similarities. Dr. Reed and his col- 
leagues are attempting to identify olfactory recep- 
tors by exploiting these similarities through a 
variety of molecular cloning approaches. 
The third component in the signal transduction 
cascade, adenylyl cyclase, is expected to be abun- 
dant in olfactory cDNA libraries. At the level of 
enzyme activity there are 10-fold higher levels of 
this protein in olfactory tissue homogenates than 
in brain tissue. In a collaboration with Dr. Alfred 
Gilman, Dr. Reed's laboratory has identified cDNA 
clones encoding three distinct forms of adenylyl 
cyclase. One of these forms appears to be ex- 
pressed exclusively in brain, and a second is ex- 
pressed in several peripheral tissues. A third form 
of the enzyme is expressed only in olfactory epithe- 
lium and is likely to represent a specialized form of 
adenylyl cyclase evolved for olfactory signal trans- 
duction. 
Elucidation of a function for the variety of forms 
of adenylyl cyclase expressed in mammalian tissues 
may prove difficult. Dr. Reed's laboratory has there- 
fore initiated experiments in Drosophila melano- 
gaster to identify homologues of the mammalian 
proteins. Among the loci that appear to encode ad- 
enylyl cyclase in Drosophila is the learning and 
memory mutant, rutabaga. The study of the molec- 
ular defect in this mutant may expand understand- 
ing of the mechanism of memory processes. 
II. Neuron Differentiation and Development. 
The olfactory neuroepithelium retains the ability 
to replace sensory neurons continually in adult ani- 
mals. This regeneration capacity provides an ideal 
opportunity to study the process of neuron differ- 
entiation and development. Dr. Reed and his col- 
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