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Received for publication April 13, 2006.
Revised June 19, 2006.
Accepted for publication June 23, 2006.
The concept of intrinsic efficacy has been enshrined in
pharmacology for a half-century, yet recent data reveal
that many ligands can differentially activate signaling
pathways mediated via a single G protein coupled receptor
(GPCR) in a manner that challenges the traditional
definition of intrinsic efficacy. Some terms for this
phenomenon include functional selectivity, agonist-
directed trafficking, and biased agonism. At the extreme,
functionally selective ligands may be both agonists and
antagonists at different functions mediated by the same
receptor. Data illustrating this phenomenon are presented
from serotonin, opioid, dopamine, vasopressin, and
adrenergic receptor systems. A variety of mechanisms may
influence this apparently ubiquitous phenomenon. It may
be initiated by differences in ligand-induced
intermediate conformational states, as shown for the 
2 adrenergic receptor. Subsequent
mechanisms that may play a role include diversity of G
proteins, scaffolding and signaling partners, and
receptor oligomers. Clearly, expanded research is needed
to elucidate the proximal (e.g., how functionally
selective ligands cause conformational changes that
initiate differential signaling), intermediate
(mechanisms that translate conformation changes into
differential signaling), and distal mechanisms
(differential effects on target tissue or organism).
Besides the heuristically interesting nature of
functional selectivity, there is a clear impact on drug
discovery, as this mechanism raises the possibility of
selecting or designing novel ligands that differentially
activate only a subset of functions of a single receptor,
thereby optimizing therapeutic action. It also may be
timely to revise classic concepts in quantitative
pharmacology and relevant pharmacological conventions to
incorporate these new concepts.
Key words:
agonist-directed trafficking, intrinsic efficacy, protean agonism, receptor conformation, receptor signaling, stimulus trafficking
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