Pleiotropic Behavior of 5‐HT2A and 5‐HT2C Receptor Agonists

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Abstract
There is now considerable evidence that a single receptor subtype can couple to multiple effector pathways within a cell. Recently, Kenakin proposed a new concept, termed “agonist‐directed trafficking of receptor stimulus”, that suggests that agonists may be able to selectively activate a subset of multiple signaling pathways coupled to a single receptor subtype. 5‐HT2A and 5‐HT2C receptors couple to phospholipase C‐(PLC) mediated inositol phosphate (IP) accumulation and PLA2‐mediated arachidonic acid (AA) release. Relative efficacies of agonists (referenced to 5‐HT) differed depending upon whether IP accumulation or AA release was measured. For the 5‐HT2C receptor system, some agonists (e.g. TFMPP) preferentially activated the PLC‐IP pathway, whereas others (e.g. LSD) favored PLA2‐AA. As expected, EC50's of agonists did not differ between pathways. For the 5‐HT2A receptor system, all agonists tested had greater relative efficacy for PLA2‐AA than for PLC‐IP. In contrast, relative efficacies were not different for 5‐HT2A agonists when sequential effects in a pathway were measured (IP accumulation vs. calcium mobilization). These data strongly support the agonist‐directed trafficking hypothesis.

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