Phospholipase A2

The 5-HT2 receptor subclass including 5-HT2C receptors, also has been shown to couple to the phospholipase A2 (PLA2) signaling cascade, which leads to the release of arachidonic acid (AA) and the subsequent production of a myriad of AA metabolites (Leysen 2004; Felder et al. 1990; Berg et al. 1996).

Berg et al. tested the capacity of a series of serotonergic ligands to differentially activate PLC and PLA2 signal transduction pathways associated with human 5-HT2A and 5-HT2C receptors transfected into CHO cells (Berg et al. 1998). The authors measured agonist-induced PLC-mediated accumulation of IP3 and PLA2-mediated release of AA simultaneously from the same population of cells and observed that the relative efficacy of a series of ligands for each of the receptors differed depending upon assessed signal transduction pathway. For the 5-HT2A receptor all tested agonists had greater relative efficacy for PLA2 than for PLC. In contrast, for the 5-HT2C receptor some agonists preferentially activated the PLC pathway, whereas others favored PLA2 when relative efficacies were referenced to 5-HT (Berg et al. 1998). These data strongly support the "agonist-directed trafficking of receptor stimulus (ADTRS)" hypothesis, which suggests that a single receptor subtype may couple with different efficacies to multiple signaling pathways depending upon the nature of the agonist to which the receptor is exposed (Kenakin 1995).

RNA-edited isoforms of the 5-HT2C receptor, 5-HT2C-VGV,and 5-HT2C-VSV, also couple to PLA2, but the potency for 5-HT to stimulate AA release was less for the edited receptors than that for the nonedited receptor (5-HT2C-INI) when receptors were expressed at similar densities (Berg et al. 2001).

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