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Murviel-lès-Montpellier, France

Lebon G.,Universites Of Montpellier Ii | Tate C.,University of Cambridge
Medecine/Sciences | Year: 2012

G protein-coupled receptors (GPCR) are the largest family of integral membrane proteins found in the plasma membrane of mammalian cells. GPCR respond to a large variety of ligands such as amines, lipids, hormones and amino-acids, which are involved in intercellular signalling events in a multitude of physiological and pathological processes. GPCRs are therefore key regulators of signal transduction by which cells respond to variations in their environment. During the last five years, striking progress has been made to solve highresolution structure of GPCR. The most recent successes are the structures of the β1 and β2 adrenoreceptors and the adenosine A2A receptor bound to a variety of agonists. Most importantly, the structure of the β2 adrenoreceptor in complex with a trimeric G protein, Gs, was recently reported. This review will present an overview of the X-ray structure determination of the GPCR and of their activation mechanism.

Bougherara H.,CNRS Laboratory of Biology and Applied Pharmacology | Georgin-Lavialle S.,University of Paris Descartes | Damaj G.,Center Hospitalier University Hopital Sud | Launay J.-M.,University Paris Diderot | And 8 more authors.
Clinical Lymphoma, Myeloma and Leukemia | Year: 2013

Background: Systemic mastocytosis (SM) is a heterogeneous disease that displays variable aggressivity. Adults with SM frequently have a D816V mutation in the tyrosine kinase (TK) receptor gene KIT. We previously reported that, in a Chinese hamster ovarian cell model expressing exogenous KIT variants, constitutive activating KIT mutations induced intracellular mislocalization of KIT reversed by inhibition of KIT TK activity. Hence, we hypothesized that inhibition of KIT kinase activity by the TK inhibitor dasatinib could be useful to increase KIT detection sensitivity in samples from patients with SM. Patients And Methods: We tested this hypothesis on a BaF/3 cell line modified to express either KIT wild-type (WT) or KIT D816V, on the human mastocytoma cell line HMC1.2, and among 28 patients with proven SM who did (n = 24) or did not (n = 4) carry the D816V KIT mutation and displayed various SM subtypes by using a simple flow cytometry assay to quantify KIT relocalization upon dasatinib treatment. Results: We confirm KIT cell surface increase upon dasatinib treatment on BaF/3 KIT D816V and HMC1.2 cell lines but not on BaF/3 KIT WT cell line. The analysis of bone marrow and peripheral blood samples of patients with SM showed KIT surface level increase for patients with the KIT D816V mutation but not for patients who had no KIT mutation. Interestingly, the extent of KIT level relocalization correlates with SM severity, with a higher relocalization for patients with aggressive forms compared with indolent forms. Conclusions: Overall, results of this study suggests that treating the peripheral blood sample with dasatinib of a patient with SM before analysis by flow cytometry could contribute to narrowing the SM diagnosis. © 2013 Elsevier Inc.

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