for rapid uncoupling of the receptors during desen- 
sitization. 
Dr. Lefkowitz and his colleagues described the 
first known inhibitors of PARK. These polyanionic 
compounds, such as heparin, provide relatively 
specific and potent inhibitors of the kinase, with 
the AT. of heparin —10 nM. A permeabilized cell sys- 
tem v^^as developed in w^hich the effects of such 
(3ARK inhibitors on the process of rapid homolo- 
' gous desensitization could be tested. Inhibitors of 
(3ARK largely ablated this process, v^^hereas inhibi- 
tors of the cAMP-dependent protein kinase or other 
protein kinases had no effect. In contrast, in this 
system inhibitors of protein kinase A blocked rapid 
heterologous desensitization. 
Transcription of the gene for the (B-adrenergic re- 
ceptor is regulated by a variety of influences. Sev- 
eral classes of steroid hormones, including andro- 
gens and glucocorticoids, appear to increase the 
rate of transcription. The rate of transcription is 
also increased by cAMP The actions of gluco- 
corticoids and cAMP appear to be mediated by fairly 
typical glucocorticoid response elements and cAMP 
response elements, respectively, found in the 5 -un- 
translated region of the p^-adrenergic receptor 
gene. Several of these modulators also appear to 
regulate the stability of the ^-adrenergic receptor 
mRNA, providing an alternate mechanism for con- 
trolling steady-state levels of P-adrenergic receptor 
mRNA. Agonist stimulation per se also leads to de- 
creases in P-adrenergic receptor mRNA, although 
the mechanism of this effect is still being worked 
out. 
II. a-Adrenergic Receptors. 
A. a^-Adrenergic receptors. The two subtypes of a^- 
adrenergic receptors that were cloned, the a^^- and 
a^g-receptors, were expressed in several eukaryotic 
expression systems. These include transient expres- 
sion in COS-7 cells, as well as permanent expression 
PUBLICATIONS 
in a fibroblast line. The transmembrane signaling sys- 
tems to which these two distinct a^-receptors were 
linked were then studied. Both subtypes potently in- 
hibit adenylate cyclase activity and more weakly stim- 
ulate phosphatidylinositol (PI) turnover. The half- 
maximal effective concentration for stimulation of PI 
turnover is ~10-fold greater than that for inhibition 
of adenylate cyclase activity. Both effects are medi- 
ated by pertussis toxin-sensitive G proteins, presum- 
ably members of the G. family. Significant differences 
in the biological activating properties of the two dif- 
ferent receptor subtypes have not yet been detected. 
B. a ^-Adrenergic receptors. The laboratory recently 
succeeded in cloning two new members of the a^- 
adrenergic receptor subfamily of adrenergic recep- 
tors. The original a^-adrenergic receptor that was 
cloned last year corresponds pharmacologically to 
the so-called a^g-receptor. Another receptor that 
corresponds to the so-called a^^-receptor has now 
been cloned. The distinction is based on pharmaco- 
logical criteria. A third member of the group has 
recently been cloned and sequenced, and the labo- 
ratory is preparing to express this gene. Both a^^- 
and ttjg-receptors appear to stimulate PI turnover 
potently. It remains to be seen what the biological 
properties of the third a^-receptor are and what the 
tissue distribution of the receptors is, as deter- 
mined by Northern blot analysis. Another question 
is whether there are additional members of the a- 
adrenergic receptor group that can be isolated by 
molecular cloning. With the advent of these new, 
previously unrecognized receptor subtypes comes 
the possibility not only for further understanding of 
receptor structure and function but for the devel- 
opment of more selective and clinically useful 
drugs. 
Dr. Lefkowitz is also James B. Duke Professor of 
Medicine and Professor of Biochemistry at the Duke 
University Medical Center. 
Books and Chapters of Books 
Caron, M.G., Bouvier, M., Hausdorff, WP, Benovic, J.L., Kobilka, B.K., Cotecchia, S., Regan, J.W , and 
Lefkowitz, R.J. 1988. The adrenergic receptors: control of hormone responsiveness by phosphorylation. 
International Conference of Second Messenger Systems in Cellular Control Prospective for New Drugs. 
London, England. 
Caron, M.G. , Hnatowich, M., Dohlman, H., Bouvier, M., Benovic, J. , O'Dowd, B.F., Kobilka, B.K. , Hausdorff, 
WP, and Lefkowitz, R.J. 1989- Structure and function of adrenergic receptors: models for understanding 
G-protein-coupled receptors. InG Proteins (Iyengar, R., and Birnbaumer, L., Eds.). Orlando, FL: Academic, 
pp 295-315. 
Continued 
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