Molecular Biology of Hormone and Drug Receptors in Health and Disease 
desensitization — the diminishing effect of drugs 
over time. This phenomenon markedly compro- 
mises the therapeutic efl&cacy of epinephrine and 
many other drugs. When drugs Hke 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. A wide variety of other circumstances 
that regulate receptor properties were also iden- 
tified, including aging, congestive heart failure, 
(S-blocker therapy, thyroid hormones, steroid 
hormones, and neoplasia. 
Our recent research is increasing our under- 
standing, in molecular terms, of how the recep- 
tors become functionally desensitized. We have 
recently discovered a new enzyme, /^-adrenergic 
receptor kinase (/3ARK), which modifies the 
structure of the receptor by introducing a phos- 
phate group. This modification may provide the 
basis for receptor desensitization. We are 
currently studying how such phosphorylation of 
the receptors by /3ARK and related enzymes modi- 
fies their function. 
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 more potent 
and specific drugs. Unraveling of the molecular 
basis of desensitization will allow the develop- 
ment of strategies for interdicting the basic reac- 
tions that lead to loss of hormone and drug effect. 
An example is the design of specific enzyme in- 
hibitors for /3ARK that could block the reactions 
leading to desensitization. Successful conclusion 
of such research may lead to methods for greatly 
prolonging and augmenting the therapeutic ac- 
tions of diverse types of drugs. 
Opposite: Desensitization of the ^-adrenergic receptor. Many pharmacological agents lose their 
effectiveness upon repeated or prolonged administration. The molecular mechanisms responsible 
for this "desensitization" may be analogous to those that underlie the loss of responsiveness 
observed in cell culture systems to hormones that activate ^-adrenergic receptor molecules. Acti- 
vation of these receptors promotes their rapid association with the a-subunit of the stimulatory G 
protein (a^. Depending on the concentration of the activating hormone, other processes are also 
triggered that eventually disrupt this association, including phosphorylation of the receptor mole- 
cule by the c AMP- dependent protein kinase (PKA ) and the ^-adrenergic receptor kinase (^ARK). 
Disruption of receptor- a ^ coupling is further ensured or maintained by interaction of the phos- 
phorylated receptor with the recently identified cytosolic protein ^-arrestin. 
From Hausdorff, W.P., Caron, M.G., and Lefkowitz, R.f. 1990. FASEBJ 4:2881-2889. 
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