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Vol. 54, Issue 1, 94-104, July 1998
Department of Pharmacology, University of Texas Health Science
Center at San Antonio, San Antonio, Texas 78284-7764 (K.A.B., W.P.C.),
Departments of
Anesthesiology (S.M.) and
Pharmacology (S.M., J.G.),
Mount Sinai School of Medicine, City University of New York, New York,
New York 10029-6574, and
Department of Pharmacology, Astra Charnwood,
Loughborough, Leics LE11 5RH, England (C.S., P.L.)
There are many examples of a single receptor coupling directly to more
than one cellular signal transduction pathway. Although traditional
receptor theory allows for activation of multiple cellular effectors by
agonists, it predicts that the relative degree of activation of each
effector pathway by an agonist (relative efficacy) must be the same. In
the current experiments, we demonstrate that agonists at the human
serotonin2A (5-HT2A) and 5-HT2C
receptors activate differentially two signal transduction pathways
independently coupled to the receptors [phospholipase C (PLC)-mediated
inositol phosphate (IP) accumulation and phospholipase A2
(PLA2)-mediated arachidonic acid (AA) release]. The
relative efficacies of agonists differed depending on which signal
transduction pathway was measured. Moreover, relative to 5-HT, some
5-HT2C agonists (e.g., 3-trifluoromethylphenyl-piperazine) preferentially activated the PLC-IP pathway, whereas others (e.g., lysergic acid diethylamide) favored the PLA2-AA pathway. In
contrast, when two dependent responses were measured (IP accumulation
and calcium mobilization), agonist relative efficacies were not
different. These data strongly support the hypothesis termed
"agonist-directed trafficking of receptor stimulus" recently
proposed by Kenakin [Trends Pharmacol Sci
16:232-238 (1995)]. Concentration-response curves to
5-HT2C agonists were fit well by a three-state model of
receptor activation, suggesting that two active receptor states may be
sufficient to explain pathway-dependent agonist efficacy. Rational drug
design that optimizes preferential effector activity within a group of
receptor-selective drugs holds the promise of increased selectivity in
clinically useful agents.
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