부산대학교 도서관

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.bcp.2008.08.024 Byline: Tim D. Werry (a), Gregory D. Stewart (a), Michael F. Crouch (b), Anne Watts (c), Patrick M. Sexton (a), Arthur Christopoulos (a) Keywords: Serotonin receptor; RNA editing; Stimulus trafficking; MAP kinase; Receptor theory Abstract: We have previously characterized a mechanism of 5HT-stimulated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation via the non-RNA-edited isoform of the serotonin 5HT.sub.2C receptor (5HT.sub.2CR-INI) in a CHO cell line. We have now used CV1 cells, which endogenously express epidermal growth factor receptors (EGFRs), to investigate whether the mechanisms underlying ERK1/2 activation by the 5HT.sub.2CR change in a time-, agonist-, and cell background-dependent manner. Interrogation of the CV1 5HT.sub.2CR-INI ERK1/2 signaling pathway, using a variety of pathway-selective inhibitors, revealed a clear time-dependence in the involvement of specific pathway components such as phosphatidylinositol 3-kinase, EGFR, matrix metalloproteases and protein kinase C. The contribution of these components to the overall response also varied with the agonist used to stimulate the receptor, providing further evidence for the ability of 5HT.sub.2CR-INI to signal in an agonist-specific manner. We also investigated the impact of 5HT.sub.2CR RNA editing on this phenomenon. Although we found no alteration in antagonist pharmacology, the partially edited VSV and fully edited VGV isoforms of the 5HT.sub.2CR exhibited altered temporal and pharmacological characteristics, including the degree of dependence on specific effectors, in signaling to ERK1/2 in comparison to the 5HT.sub.2CR-INI. In conclusion, we provide evidence for remarkable flexibility in 5HT.sub.2CR-mediated ERK1/2 signaling that can be pharmacologically and mechanistically distinct depending on the agonist or edited isoform involved and on the duration of receptor activation. Author Affiliation: (a) Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia (b) TGR BioSciences, Thebarton, South Australia 5031, Australia (c) Leiden/Amsterdam Center for Drug Research, PO Box 9502, Leiden 2300RA, The Netherlands Article History: Received 27 June 2008; Accepted 25 August 2008