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Effector pathway-dependent relative efficacy at serotonin type 2A and 2C receptors: evidence for agonist-directed
K A Berg1, S Maayani, J Goldfarb
1Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7764, USA.
Abstract:
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.
Insights
Agonists activate serotonin receptors differently across signaling pathways, challenging traditional receptor theory. This discovery supports "agonist-directed trafficking" and aids rational drug design for targeted therapies.
Area of Science:
- Pharmacology
- Molecular Biology
- Biochemistry
Background:
- Single receptors can couple to multiple signal transduction pathways.
- Traditional receptor theory posits uniform relative efficacy across effectors for a given agonist.
- Deviations from this prediction suggest complex receptor activation mechanisms.
Purpose of the Study:
- To investigate whether agonists exhibit differential relative efficacies at serotonin 5-HT2A and 5-HT2C receptors across distinct signal transduction pathways.
- To test the hypothesis of "agonist-directed trafficking of receptor stimulus".
Main Methods:
- Studied agonists at human serotonin 5-HT2A and 5-HT2C receptors.
- Measured phospholipase C (PLC)-mediated inositol phosphate (IP) accumulation and phospholipase A2 (PLA2)-mediated arachidonic acid (AA) release.
- Analyzed concentration-response curves using a three-state receptor activation model.
Main Results:
- Agonists showed differing relative efficacies for PLC-IP and PLA2-AA pathways, independent of receptor type.
- Specific agonists demonstrated preferential activation of either the PLC-IP or PLA2-AA pathway.
- No difference in relative efficacy was observed when measuring dependent responses (IP accumulation and calcium mobilization).
Conclusions:
- Data support the "agonist-directed trafficking of receptor stimulus" hypothesis.
- A three-state receptor model can explain pathway-dependent agonist efficacy.
- Optimizing pathway-selective drugs through rational drug design offers potential for increased clinical selectivity.