Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors

The type 2 serotonin (5-HT2) receptor subfamily is known to couple to phosphoinositide hydrolysis (PI) and the subsequent mobilization of intracellular Ca2+, as well as the release of arachidonic acid (AA). Less is known of 5-HT2-mediated activation of the mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase (ERK1/2) signaling. The present study measured the relative efficacies and potencies of 5-HT agonists to activate ERK2 in non-neuronal cells expressing recombinant human 5-HT2A, 5-HT2B, and 5-HT2C(ISV) receptors. 5-HT agonists stimulated ERK2 activity via all three 5-HT2 subtypes. There were no meaningful differences in the potencies or relative efficacies of these agonists to affect ERK2 activity vs. PI accumulation or Ca2+ mobilization, suggesting that these pathways may be sequentially linked. Indeed, ERK2 activity was very sensitive to PKC inhibition and calcium chelation and insensitive to tyrosine kinase and PI-3-kinase inhibition. 5-HT2 receptors efficiently couple to MAPK activation via sequential PI hydrolysis, and Ca2+ mobilization. This profile differs from reports of “agonist-directed trafficking of receptor stimulus” between PI/Ca2+ and AA pathways activated by 5-HT2 receptors.