title: Pharmacological characterization of mitogen-activated protein kinase activation by recombinant human 5-HT2C, 5-HT2A, and 5-HT2B receptors.
abstract: The type 2 serotonin (5-HT(2)) receptor subfamily is known to couple to phosphoinositide hydrolysis (PI) and the subsequent mobilization of intracellular Ca(2+), as well as the release of arachidonic acid (AA). Less is known of 5-HT(2)-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-HT(2A), 5-HT(2B), and 5-HT(2C(ISV)) receptors. 5-HT agonists stimulated ERK2 activity via all three 5-HT(2) subtypes. There were no meaningful differences in the potencies or relative efficacies of these agonists to affect ERK2 activity vs. PI accumulation or Ca(2+) 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-HT(2) receptors efficiently couple to MAPK activation via sequential PI hydrolysis, and Ca(2+) mobilization. This profile differs from reports of "agonist-directed trafficking of receptor stimulus" between PI/Ca(2+) and AA pathways activated by 5-HT(2) receptors.
authors.affiliation: Department of Neuroscience Biology, Pfizer Global Research and Development, Pfizer Inc., Eastern Point Road, Groton, CT 06340, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Knauer
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Campbell
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Chio
authors.forename: Lawrence W
authors.initials: LW
authors.lastname: Fitzgerald
mesh_terms: D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D010716:Phosphatidylinositols / Q000378:metabolism; D011485:Protein Binding; D011869:Radioligand Assay; D044402:Receptor, Serotonin, 5-HT2A / Q000096:biosynthesis / Q000502:physiology*; D044403:Receptor, Serotonin, 5-HT2B / Q000096:biosynthesis / Q000502:physiology*; D044405:Receptor, Serotonin, 5-HT2C / Q000096:biosynthesis / Q000502:physiology*; D011994:Recombinant Proteins / Q000096:biosynthesis; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
chemical_list: D010716:Phosphatidylinositols; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011994:Recombinant Proteins; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D002118:Calcium