Characterization of serotonin 5‐HT2C receptor signaling to extracellular signal‐regulated kinases 1 and 2

• Published in: Journal of neurochemistry 2005-06, Vol.93 (6), p.1603-1615
• Main Authors: Werry, Tim D., Gregory, Karen J., Sexton, Patrick M., Christopoulos, Arthur
• Format: Article
• Language: English
• Subjects: 5HT; Animals; antipsychotic; Biological and medical sciences; Calcium Signaling - physiology; Cell receptors; Cell structures and functions; CHO Cells; Cricetinae; Diglycerides - metabolism; Endocytosis - physiology; Enzymes; Fundamental and applied biological sciences. Psychology; G proteins; Humans; inverse agonist; Ligands; map kinase; MAP Kinase Signaling System - physiology; Medical sciences; Metabolic diseases; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Molecular and cellular biology; Monoamines receptors (catecholamine, serotonine, histamine, acetylcholine); Neurons; Neurotransmitters; Obesity; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositols - metabolism; Phospholipase D - metabolism; Phospholipases A - metabolism; phospholiphase D; Phosphorylation; Protein-Tyrosine Kinases - metabolism; Receptor, Serotonin, 5-HT1B - genetics; Receptor, Serotonin, 5-HT1B - metabolism; Receptor, Serotonin, 5-HT2C - genetics; Receptor, Serotonin, 5-HT2C - metabolism; Signal transduction; Transfection; Type C Phospholipases - metabolism
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2005.03161.x

Serotonin 5‐HT2C receptors (5‐HT2CRs) are almost exclusively expressed in the CNS, and implicated in disorders such as obesity, depression, and schizophrenia. The present study investigated the mechanisms governing the coupling of the 5‐HT2CR to the extracellular signal‐regulated kinases (ERKs) 1/2, using a Chinese hamster ovary (CHO) cell line stably expressing the receptor at levels comparable to those found in the brain. Using the non‐RNA‐edited isoform of the 5‐HT2CR, constitutive ERK1/2 phosphorylation was observed and found to be modulated by full, partial and inverse agonists. Interestingly, agonist‐directed trafficking of receptor stimulus was also observed when comparing effects on phosphoinositide accumulation and intracellular Ca2+ elevation to ERK1/2 phosphorylation, whereby the agonists, [±]‐2,5‐dimethoxy‐4‐iodoamphetamine (DOI) and quipazine, showed reversal of efficacy between the phosphoinositide/Ca2+ pathways, on the one hand, and the ERK1/2 pathway on the other. Subsequent molecular characterization found that 5‐HT‐stimulated ERK1/2 phosphorylation in this cellular background requires phospholipase D, protein kinase C, and activation of the Raf/MEK/ERK module, but is independent of both receptor‐ and non‐receptor tyrosine kinases, phospholipase C, phosphoinositide 3‐kinase, and endocytosis. Our findings underscore the potential for exploiting pathway‐selective receptor states in the differential modulation of signaling pathways that play prominent roles in normal and abnormal neuronal signaling.