Chemical Communication 
Michael R. Lemer, M.D., Ph.D. — Associate Investigator 
Dr. Lemer is also Associate Professor in the Departments of Internal Medicine and of Pharmacology and 
the Child Study Center at Yale University School of Medicine. He obtained his B.A. degree in chemistry 
from the University of Pennsylvania and his M.D. and Ph.D. degrees from Yale. His doctoral research, with 
Joan Steitz, was on small nuclear ribonucleoproteins (snRNPs). He interned in internal medicine at 
Barnes Hospital, St. Louis, and did postdoctoral research in neurobiology at Washington University with 
Gerald Fischbach before returning to Yale. His honors include the George Herbert Hitchings Award for 
innovative methods in drug design. 
INTRASPECIES communication via specific 
chemical messengers is widely employed 
throughout the animal kingdom. Among the com- 
mon uses of chemical communication are mark- 
ing of territory, signaling danger, and indicating 
sources of food. A particularly striking example is 
the use of sex pheromones. Here, animals release 
a defined blend of related molecules that trigger 
distinct mating behaviors in members of the op- 
posite sex. For detection to occur, three criteria 
must be satisfied. Molecules of the pheromone 
must reach olfactory receptors, must interact 
with them, and must be inactivated so that subse- 
quent molecules can be detected. 
Past research has focused on the problems of 
chemical transport to olfactory receptors and in- 
activation of these molecules. Moths — particu- 
larly Manduca sexta and Antheraea polyphe- 
mus — have provided excellent models. Many of 
the olfactory receptor cells of the male M. sexta 
and most of those from the male A. polyphemus 
are specialized for detecting sex pheromone. For 
both animals, the pheromone-binding proteins, 
which solubilize molecules of the pheromone 
blend and carry them to receptors, have been 
characterized. In addition, a family of general 
odorant-binding proteins, which are related to 
the ones employed by the moths to carry phero- 
mone, has been discovered and characterized. 
Likewise, the enzymes that rapidly and specifi- 
cally inactivate pheromone molecules and are ap- 
parently requisite to the sensory apparatus em- 
ployed by males to locate females, have been 
investigated at the biochemical level. For M. 
sexta, in which both major components of the 
pheromone blend are aldehydes, a single en- 
zyme, an aldehyde oxidase, suffices, while A. 
polyphemus employs both an aldehyde oxidase 
and an esterase because its pheromone compo- 
nents include both an aldehyde and an ester. Our 
research has now turned to developing methods 
for investigating olfactory receptors themselves. 
Over the past few years many laboratories have 
conducted biochemical, electrophysiological, 
and molecular cloning experiments concerned 
with the nature of signal transduction by olfac- 
tory receptors. Depending on the animal whose 
sense of smell is being investigated, the results 
indicate that either cAMP, IP3/DAG (IP3, inositol 
1,4,5-trisphosphate; DAG, diacylglycerol) , or 
both second messenger systems are involved. It 
now appears that the study of olfaction, and 
hence a major aspect of chemical communication 
between animals, is part of the general problem 
of how G protein-coupled receptors work. 
At the present time, several methods are em- 
ployed to study how receptors that regulate intra- 
cellular concentrations of cAMP or IP3/DAG 
work, such as adenylate cyclase assays, radioim- 
munoassays, measurements of IP3 or DAG, moni- 
toring the flow of ions through channels in frog 
oocyte membranes, or looking at changes in in- 
tracellular calcium concentrations via appro- 
priate fluorescent indicators. To study G pro- 
tein-coupled receptors, and ones relevant to 
olfaction in particular, we are developing a new 
method for monitoring receptor stimulation that 
can track changes in intracellular concentrations 
of cAMP or IP3/DAG in over 10,000 individual 
cells simultaneously. 
To follow changes in cAMP or IP3/DAG levels 
in many individual cells at the same time, we 
have turned to that ability of some animals to 
change colors rapidly. In nature, color changes 
are used for such purposes as camouflage and the 
communication of states of emotion. Among ver- 
tebrates, quick color alterations are brought 
about by the controlled movement of pigment 
granules within chromatophores. When pigment 
granules in melanophores (a particular type of 
chromatophore) are aggregated, the animal ap- 
pears light, and when pigment is dispersed, the 
animal appears dark. It turns out that the pigment 
translocation apparatus is controlled via second 
messenger systems that are themselves regulated 
by G proteins. As a result, the state of pigment 
disposition within melanophores reflects the 
state of activity of G protein-coupled receptors. 
Recently the laboratory has successfully har- 
nessed frog melanophores as the center of an 
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