GPCR DESENSITIZATION

Constitutive receptor desensitization as molecular mechanism underlying cardia bifida

 Coordinatore UNIVERSITAET ULM 

 Organization address address: HELMHOLTZSTRASSE 16
city: ULM
postcode: 89081

contact info
Titolo: Mr.
Nome: Frank
Cognome: Gleixner
Email: send email
Telefono: +49 731 50066397
Fax: +49 731 50066392

 Nazionalità Coordinatore Germany [DE]
 Totale costo 75˙000 €
 EC contributo 75˙000 €
 Programma FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
 Code Call FP7-PEOPLE-2010-RG
 Funding Scheme MC-IRG
 Anno di inizio 2010
 Periodo (anno-mese-giorno) 2010-12-01   -   2013-11-30

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    UNIVERSITAET ULM

 Organization address address: HELMHOLTZSTRASSE 16
city: ULM
postcode: 89081

contact info
Titolo: Mr.
Nome: Frank
Cognome: Gleixner
Email: send email
Telefono: +49 731 50066397
Fax: +49 731 50066392

DE (ULM) coordinator 75˙000.00

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

signal    protein    heart    zebrafish    gpcrs    mutation    cardia    grks    bifida       dry    gpcr    receptors    receptor    arrestins       constitutively    family    proteins    point    cell    beta       acid    motif    tm   

 Obiettivo del progetto (Objective)

'7TM receptors are called GPCRs because they require interaction with heterotrimeric G proteins to signal. In humans the family of GPCRs is comprised of more than 800 members. Despite their large number, GPCRs share high sequence homology and rely on an amazingly small assortment of accessory molecules to regulate their ability to signal. One such regulatory protein family is the family of G protein-coupled receptor kinases (GRK), which consists of seven isoforms. GRKs provide the rate limiting mechanism for terminating incoming signals at the receptor to protect the cell from over-stimulation. Phosphorylation of the activated GPCR by GRKs is a prerequisite that not only commits the receptor to desensitize (separation from G protein) but also directs its association with a group of adaptor proteins termed arrestins and with the internalization machinery. The E/DRY (glutamic acid/aspartic acid, arginine, tyrosine) motif located at the end of the third transmembrane helix of GPCRs has been shown to be of particular importance for the execution of G protein-dependent signaling: Selective mutation of the R evidently triggers not only hyperphosphorylation by GRKs, but also the uncoupling of the G protein. Such mutated receptors constitutively associate with beta-arrestin and are localized to endosomal compartments. Zebrafish harboring a point mutation in the E/DRY motif of the 7TM sphingosine 1 phosphate receptor 2 (S1P2) develop a cardia bifida, a detrimental defect seen in heart development as it is characterized by the formation of two heart cylinders instead of one. We assume that the R150H point mutation of S1P2 results in a GPCR that is unresponsive to its ligand and constitutively inactive. Thus, the aim of this study is to investigate, if the cardiac phenotype of these embryos is caused by constitutive desensitization of S1P2 (R150H) and if it could be rescued by inhibiting GRKs and beta-arrestins, which spatially separate the receptor from its G protein.'

Introduzione (Teaser)

Developmental processes entail a carefully controlled interplay of cell signalling, cell growth and differentiation that ensure the development of a new organism. European researchers investigated the molecular aetiology of the embryonic malformation cardia bifida using zebrafish.

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