Pleiotropic behavior of 5-HT2A and 5-HT2C receptor agonists

Ann N Y Acad Sci. 1998 Dec 15;861:104-10. doi: 10.1111/j.1749-6632.1998.tb10180.x.


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.

Publication types

  • Review

MeSH terms

  • Animals
  • GTP-Binding Proteins / physiology
  • Inositol Phosphates / metabolism
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology*
  • Serotonin Receptor Agonists / pharmacology*
  • Signal Transduction
  • Type C Phospholipases / metabolism


  • Inositol Phosphates
  • Receptor, Serotonin, 5-HT2A
  • Receptor, Serotonin, 5-HT2C
  • Receptors, Serotonin
  • Serotonin Receptor Agonists
  • Type C Phospholipases
  • GTP-Binding Proteins