Molecular Biology of Hormone and Drug Receptors in Health and Disease 
over time. This phenomenon markedly compro- 
mises the therapeutic efficacy of epinephrine and 
many other drugs. When drugs like epinephrine 
combine with their receptors, they not only stim- 
ulate them but also produce changes that impair 
their function, thus leading to desensitization. 
These changes involve an actual loss of receptors 
from the cell surface (they move inside the cell 
where they cannot function) and a chemical 
change of those receptors remaining at the cell 
surface so that they function less effectively. With 
fewer functioning receptors present at their sur- 
face, cells are less able to respond to drugs or 
hormones. 
Our recent research is increasing our under- 
standing, in molecular terms, of how the recep- 
tors become functionally desensitized. We have 
discovered two new proteins that function to de- 
sensitize the receptors. The first is an enzyme, the 
jS-adrenergic receptor kinase (/3ARK) , which mod- 
ifies the structure of the receptors by introducing 
a phosphate group when the receptors are stimu- 
lated. The second is the protein /3-arrestin, which 
binds to the phosphorylated receptors and pre- 
vents them from acting. Both proteins are widely 
distributed at synapses throughout the central 
nervous system, suggesting their actions are not 
limited to the j8-adrenergic receptors. 
The implications of such fundamental research 
on receptors for clinical medicine are profound. 
Elucidation of the detailed structure of the recep- 
tors will allow the precise design of drugs that are 
more potent and specific. Unraveling of the mo- 
lecular basis of desensitization will allow the de- 
velopment of strategies for interdicting the basic 
reactions that lead to loss of hormone and drug 
effect. An example is the design of specific en- 
zyme inhibitors for ^ARK that could block the 
reactions leading to desensitization. Successful 
conclusion of such research may lead to methods 
for greatly prolonging and augmenting the thera- 
peutic actions of diverse types of drugs. 
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