The Diversity of Receptor Function 
Richard Axel, M.D. — Investigator 
Dr. Axel is also Higgins Professor of Biochemistry and Pathology at Columbia University College of Phy- 
sicians and Surgeons. He received his undergraduate degree from Columbia College and his M.D. degree 
from the Johns Hopkins University School of Medicine. He then came to Columbia University as a resident 
in pathology at the College of Physicians and Surgeons. He held research fellowships in Columbia's Insti- 
tute of Cancer Research, with Sol Spiegelman, and the Department of Pathology. Dr. Axel is a member of 
the National Academy of Sciences. Among his many honors are the Eli Lilly Award in Biological Chemistry 
and the Richard Lounsbery Award from the National Academy of Sciences. 
ALL cells communicate with their environ- 
ment by the interaction of exogenous mole- 
cules with receptor molecules on the cell sur- 
face. This activates one of many possible 
intracellular signaling pathways by which infor- 
mation from the environment is decoded to elicit 
an appropriate response by individual cells or by 
the organism. Olfaction provides a particularly 
clear example of the organism's ability to recog- 
nize and discriminate a vast array of environmen- 
tal signals, in this case the molecules perceived as 
odors. 
The cellular immune system provides an exam- 
ple of the organism's ability to respond to diverse 
foreign substances within the internal environ- 
ment. These two systems pose the problem of 
how cells encode sufficient information to recog- 
nize and respond to a highly diverse array of sig- 
naling molecules. Our laboratory has addressed 
these problems by analyzing the structure and 
function of the genes encoding the specific re- 
ceptor molecules in the immune system, the ol- 
factory system, and the brain. 
The Molecular Biology of Smell 
Vertebrates have evolved an extremely sensi- 
tive mechanism to detect and discriminate a rich 
diversity of odors. The detection of chemically 
distinct odors results from the specific associa- 
tion of odorous signaling molecules with discrete 
receptors on olfactory neurons. These neurons, 
which reside within the epithelium of the nose, 
then transmit the information directly to the 
brain. Thus the detection of odors is restricted to 
the olfactory neuron, whereas the discrimination 
of distinct odors requires neural processing in the 
olfactory bulb and cerebral cortex. 
To address the question of how the organism is 
capable of recognizing more than 10,000 dis- 
crete odors, we have recently cloned a large fam- 
ily of genes likely to encode an extremely large 
number of olfactory receptors. We have isolated a 
multigene family encoding a vast array of recep- 
tor molecules that traverse the membrane seven 
times. Expression of this gene family is restricted 
to the olfactory epithelium. 
The family comprises more than 200 members, 
representing one of the largest gene families in 
the eukaryotic chromosome. All the genes are 
characterized by sequence and structural motifs 
shared by all members of the gene family, but the 
individual genes each exhibit regions of signifi- 
cant sequence divergence. Analysis of the se- 
quences of the members of the family of putative 
olfactory receptors provides insight into how the 
family has been generated in evolutionary time 
and how these genes diverge to accommodate rec- 
ognition of a large array of odorants. 
Isolation of the family of genes encoding the 
receptor molecules immediately provides one 
solution to the problem of olfactory perception: 
How do we recognize so many odors? On one 
extreme, we could argue that the recognition of 
diverse odorants could be accomplished by a 
small number of promiscuous receptors each ca- 
pable of interaction with several structurally dis- 
tinct odor molecules. Alternatively, olfactory 
perception could result from a large number of 
different receptor molecules each capable of in- 
teracting with one or a small number of specific 
odorants. The size of the gene family we have 
characterized suggests that there are indeed a 
very large number of odorant receptors, each ca- 
pable of interacting with a small number of odor- 
ous ligands. 
These observations are in sharp contrast to 
other sensory systems, such as vision or touch, 
where discrimination of sensory information is 
accomplished by a rather small number of recep- 
tor modalities. 
In a separate series of experiments, we have 
asked how the association of an odorant with its 
receptor can generate an action potential trans- 
mitted to the brain. Recent evidence from other 
laboratories suggests that olfactory receptors ac- 
tivate second messenger systems, leading to an 
elevation in intracellular cyclic nucleotides. We 
and others have cloned a gene encoding a cyclic, 
nucleotide-gated ion channel that is unique to 
23 
