@article {Deraet983, author = {Maud Deraet and Philippe Manivet and Agnes Janoshazi and Jacques Callebert and Silke Guenther and Ludovic Drouet and Jean-Marie Launay and Luc Maroteaux}, title = {The Natural Mutation Encoding a C Terminus-Truncated 5-Hydroxytryptamine2B Receptor Is a Gain of Proliferative Functions}, volume = {67}, number = {4}, pages = {983--991}, year = {2005}, doi = {10.1124/mol.104.008268}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Although potentially implicated in several physiological functions, few functional mutations have been identified in the human 5-hydroxytryptamine (HT)2B receptor gene. A heterozygous mutation R393X in the 5-HT2B receptor was recently identified in a patient diagnosed with pulmonary hypertension after intake of the anorexigenic dexfenfluramine. Although reported to generate a lack of function, this C terminus-truncated 5-HT2B receptor should somehow affect transduction pathways relevant to pulmonary hypertension. In our study, we investigated putative modifications in transduction of the R393X-mutated 5-HT2B receptor. In stably transfected cells, we confirmed the loss of inositol 1,4,5-trisphosphate stimulation caused by the Gαq uncoupling, despite conserved ligand affinity between the normal and mutated receptors. We also observed a partial loss of nitric-oxide synthase stimulation. However, the truncated R393X receptor presented 1) a strong gain of efficacy in cell proliferation as assessed by mitogen-activated protein kinase activity and thymidine incorporation, 2) a preferential coupling to Gα13 as shown by blocking antiserum, and 3) an apparent lack of internalization upon agonist stimulation as observed by confocal microscopy. This work demonstrates that, in the 5-HT2B receptor, the C terminus, including the palmitoylation and phosphorylation sites, is absolutely required for proper transduction and internalization. For the first time, we show that the lack of C terminus can generate a switch of coupling to Gα13, a reduced NO synthase activation, and an increase in cell proliferation. All these modifications are relevant in pathophysiological vasoconstriction.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/67/4/983}, eprint = {https://molpharm.aspetjournals.org/content/67/4/983.full.pdf}, journal = {Molecular Pharmacology} }