TY - JOUR T1 - The Natural Mutation Encoding a C Terminus-Truncated 5-Hydroxytryptamine<sub>2B</sub> Receptor Is a Gain of Proliferative Functions JF - Molecular Pharmacology JO - Mol Pharmacol SP - 983 LP - 991 DO - 10.1124/mol.104.008268 VL - 67 IS - 4 AU - Maud Deraet AU - Philippe Manivet AU - Agnes Janoshazi AU - Jacques Callebert AU - Silke Guenther AU - Ludovic Drouet AU - Jean-Marie Launay AU - Luc Maroteaux Y1 - 2005/04/01 UR - http://molpharm.aspetjournals.org/content/67/4/983.abstract N2 - 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. ER -