Molecular Biology of Hormone and Drug 
Receptors in Health and Disease 
Robert J. Lefkowitz, M.D. — Investigator 
Dr. Lefkowitz 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, the NIH, and Massachusetts 
General Hospital. As a molecular pharmacologist he has focused on the molecular structure and regula- 
tory mechanisms controlling the function of the adrenergic receptors that mediate the actions of cate- 
cholamines. Dr. Lefkowitz has received numerous awards, including the Gairdner Foundation Interna- 
tional 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 several distinct subtypes of adren- 
ergic receptors: aj, a-^^, and /32- 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. They mediate 
physiological responses as diverse as changes in 
blood pressure, changes in heart rate and contrac- 
tility, and alterations in the metabolism of glu- 
cose. Drugs that interact with them are among the 
most effective agents used to treat various forms 
of heart disease, hypertension, asthma, shock, 
and depression. Research on these "exemplary" 
receptors has important implications for under- 
standing 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 recently developed recombi- 
nant DNA or gene-cloning techniques. These per- 
mit isolation of the genes for the receptors, 
which in turn permits their complete primary 
amino acid sequences to be deduced. 
We have recently isolated the genes for all of 
the known adrenergic receptors {a^, a^, jSj, 182). 
as well as a number of closely related receptors, 
and determined their complete sequences. Re- 
markably, 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 mechanisms by which signals 
as divergent as a photon of light and a drug mole- 
cule like epinephrine elicit their characteristic 
biochemical and physiologic responses. By vary- 
ing the structure of the gene and hence the recep- 
tor protein that it produces, we can define which 
structural features of the receptor molecule de- 
termine its characteristic functions. 
An unexpected result of the cloning of the four 
main types of adrenergic receptor genes was the 
discovery of the genes for several novel subtypes 
of adrenergic receptors not previously known to 
exist. Knowledge of these new receptors opens 
the way for the development of drugs with 
greater selectivity and fewer side effects. Such 
drugs might conceivably have applications in the 
treatment of such disparate diseases as hyperten- 
sion, asthma, diabetes, and prostatism, or even in 
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 
273 
