Adrenergic Receptor Structure and Function 
Brian K. Kobilka, M.D. — Assistant Investigator 
Dr. Kobilka is also Assistant Professor of Medicine, Cardiology, and Molecular and Cellular Physiology at 
the Stanford University Medical Center. He received his undergraduate degree in biology and chemistry 
from the University of Minnesota, Duluth, and his M.D. degree from Yale University. After his residency 
in internal medicine at Barnes Hospital, St. Louis, he joined the laboratory of Robert Lefkowitz as a 
research fellow in cardiology at Duke University. Four years later he was appointed Assistant Professor in 
the Department of Medicine at Duke University, and the following year he assumed his present position 
at Stanford. 
THE autonomic nervous system serves as the 
master control center for the cardiovascular 
system. It monitors the effectiveness of the latter 
system in providing nutrients and oxygen to the 
rest of the body and appropriately adjusts the 
heart rate, blood pressure, and blood flow. These 
adjustments are made via nerves that serve the 
heart, blood vessels, and kidneys. 
Adrenergic receptors form the interface be- 
tween these nerves (of the sympathetic subsys- 
tem) and the organs they innervate. Catechol- 
amines released from sympathetic nerve 
terminals bind to adrenergic receptors on the sur- 
face of target cells, and the activated receptors 
modify the function of these cells. 
When a catecholamine occupies its binding 
site, the receptor activates a GTP-binding protein 
(G protein) inside the cell. The activated G pro- 
tein may then modulate the activity of a cellular 
en2yme or ion channel. The genes (or corre- 
sponding cDNAs) for nine types of adrenergic re- 
ceptors have been cloned. There are three types 
of ttj-adrenergic receptors, three types of 
adrenergic receptors, and three types of |8 recep- 
tors. All of these receptors are structurally simi- 
lar, having seven hydrophobic domains that are 
thought to be membrane spanning. These fea- 
tures are shared by other receptors that activate G 
proteins. 
a2-Adrenergic Receptor Subtype Diversity 
The role played by the aj-, a2-, and /S-adrener- 
gic receptors in the function of the sympathetic 
nervous system has been extensively studied. 
Adrenergic receptors are involved in blood pres- 
sure control and in directing blood flow to spe- 
cific tissues. However, the physiological role of 
each of the three a2 receptor types is not known. 
This is in part due to the lack of highly selective 
drugs that can activate or inhibit each type of 
adrenergic receptor. We are attempting to iden- 
tify distinctive functional and physiological prop- 
erties for each of the different a2 receptors. These 
studies may provide incentive for the develop- 
ment of more highly selective a2'^drenergic re- 
ceptor drugs for the treatment of hypertension 
and vascular disease. 
Adrenergic Receptor Structure 
A major focus in my laboratory is to learn more 
about the three-dimensional structure of adrener- 
gic receptors and to determine how they transmit 
signals across the cell membrane's lipid bilayer. 
We are taking several approaches to study the re- 
ceptor structure. Over the past year our mutagen- 
esis studies have identified a specific amino acid 
in the /Jj-adrenergic receptor that forms part of 
the binding site for a large class of /3 receptor- 
blocking drugs. When this amino acid is placed in 
an a2 receptor, it confers the ability to bind to 
these (8 receptor drugs. We have also used muta- 
genesis studies to identify intramolecular interac- 
tions within ^2- ^rid a2-adrenergic receptors. This 
information is useful in developing models for 
the three-dimensional structure of the receptor. 
A long-range goal is to study the three- 
dimensional structure of the /32-3drenergic re- 
ceptor, using techniques that provide high- 
resolution pictures of this protein or detect 
changes in the structure of the receptor during 
signal transduction. These techniques require 
large quantities of pure, functional receptor pro- 
tein. Using recombinant DNA techniques, we 
have made several modifications in the structure 
of the /32-adrenergic receptor that lead to in- 
creased expression in cultured cells. Our goal 
during the next year will be to refine the purifica- 
tion procedure to optimize the yield and mini- 
mize the cost of large-scale production of recep- 
tor protein. 
Receptor Biosynthesis 
The primary amino acid sequence of a receptor 
contains all the essential information needed for 
the receptor's proper folding, post-translational 
processing, and cellular targeting. Understanding 
the process by which receptors are folded and 
processed should provide insights into receptor 
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