Linked Life Data

15625277

Source:http://linkedlifedata.com/resource/pubmed/id/15625277

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2005-3-22
pubmed:abstractText
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-HT(2B) 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-HT(2B) receptor should somehow affect transduction pathways relevant to pulmonary hypertension. In our study, we investigated putative modifications in transduction of the R393X-mutated 5-HT(2B) receptor. In stably transfected cells, we confirmed the loss of inositol 1,4,5-trisphosphate stimulation caused by the G(alphaq) 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 G(alpha13) 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-HT(2B) 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 G(alpha13), a reduced NO synthase activation, and an increase in cell proliferation. All these modifications are relevant in pathophysiological vasoconstriction.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Apr
pubmed:issn
0026-895X
pubmed:author
pubmed:issnType
Print
pubmed:volume
67
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
983-91
pubmed:dateRevised
2011-10-27
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
The natural mutation encoding a C terminus-truncated 5-hydroxytryptamine 2B receptor is a gain of proliferative functions.
pubmed:affiliation
INSERM U616 Hospital Pitié-Salpetrière, Batiment Pédiatrie, 47 boulevard de l'Hôpital, 75651 Paris Cedex 13, France.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't