Molecular Biology of Hormone and Drug Receptors 
in Health and Disease 
Robert J. Lefkowitz, M.D. — Investigator 
Dr. Lefltowitz is also James B. Duke Professor of Medicine and of Biochemistry at the Duke University 
Medical Center. He received his B.A. ( chemistry) and M.D. degrees from Columbia University and clinical 
and research training at Columbia- Presbyterian Medical Center in New York, NIH, and Massachusetts 
General Hospital. As a molecular pharmacologist he has focused on the molecular structure and 
regulatory mechanisms controlling the function of the adrenergic receptors that mediate the actions of 
catecholamines. Dr. Lefkowitz has received numerous awards, including the Gairdner Foundation 
International Award. He is a member of the National Academy of Sciences. 
OUR research program is concerned with the 
molecular properties and regulatory mecha- 
nisms that control the function of plasma mem- 
brane receptors for hormones and drugs under 
normal and pathological circumstances. Recep- 
tors are the cellular macromolecules with which 
biologically active substances (e.g., hormones, 
drugs, neurotransmitters, growth factors, viruses, 
lipoproteins) initially interact. Such receptors 
perform two essential functions: 1) They receive 
or bind these biologically active substances at the 
surface of the cell. 2) They transmit the sub- 
stance's message into the cell, thus influencing 
its metabolic activity and function. 
We have utilized the receptors for epinephrine 
(adrenaline) and related compounds, which are 
generally termed adrenergic receptors, as models 
for the study of receptors. Such receptors are 
found throughout the brain, heart, smooth mus- 
cle cells, and most other cells of the human organ- 
ism. There are at least nine distinct subtypes of 
adrenergic receptors (aj, a-^, 182, etc.). These 
receptors interact not only with endogenous epi- 
nephrine and norepinephrine but with a variety 
of clinically important drugs. 
We have studied these particular receptors for 
several reasons: they are more widely distributed 
than perhaps any other type of receptor, they are 
exemplary of each of the major biochemical 
pathways by which receptors are known to signal 
to the interior of the cell, and they are clinically 
and therapeutically significant. These receptors 
mediate physiological responses as diverse as 
changes in blood pressure, changes in heart rate 
and contractility, and alterations in the metabo- 
lism of glucose. Drugs that interact with these 
receptors are among the most effective agents 
used to treat various forms of heart disease, hy- 
pertension, asthma, shock, and depression. Re- 
search on these exemplary receptors has impor- 
tant implications for understanding hormone and 
drug receptor interactions generally and the 
mechanisms by which they are regulated. 
Our research is focused on several intimately 
related goals. First, we wish to understand, in de- 
tailed molecular terms, the biochemical nature 
of the receptors. This is being accomplished by 
the application of recombinant DNA or gene- 
cloning techniques. These permit isolation of the 
genes for the receptors, which in turn permits 
their complete primary amino acid sequences to 
be deduced. 
We have isolated the genes for all of the known 
adrenergic receptors, as well as a number of 
closely related receptors, and determined their 
complete sequences. Remarkably, the structures 
of these receptors are similar to each other and to 
that of the visual light receptor rhodopsin. This 
insight is helping to clarify the general mecha- 
nisms by which signals as divergent as a photon of 
light and a drug molecule like epinephrine elicit 
their characteristic biochemical and physiologi- 
cal responses. By varying the structure of the gene 
and hence the receptor protein that it produces, 
we can define which structural features of the 
receptor molecule determine its characteristic 
functions. 
An unexpected result of the cloning of the 
known types of adrenergic receptor genes was 
the discovery of the genes for several novel sub- 
types of adrenergic receptors not previously 
known to exist. Knowledge of these new recep- 
tors opens the way for the development of new 
drugs with greater selectivity and fewer side ef- 
fects. Such drugs might conceivably have appli- 
cations in the treatment of such disparate diseases 
as hypertension, asthma, diabetes, and prostat- 
ism, or even as novel anesthetic agents. 
A second current research goal is to elucidate 
the patterns of receptor regulation. One of the 
most important insights to come from our studies 
of receptors is that their properties are not fixed. 
Rather, the properties of the receptors are in- 
fluenced by the hormones and drugs with which 
they interact, as well as by a variety of disease 
states. 
There are important clinical implications of 
the ever-changing nature of the receptors. For ex- 
ample, this provides a basis for beginning to un- 
derstand the phenomenon of drug tolerance or 
desensitization, the diminishing eff^ect of drugs 
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