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Séminaire - Bernd NuernbergDissecting hormonal pathways in Gai-mutant mouse models

Abstract :

Seven transmembrane (7TM) receptors (also called G-protein-coupled receptor, GPCR) are encoded by more than 1000 members, the largest superfamily of the human genome. Some two hundred serve as binding proteins for hormones and neurotransmitters and are involved in (patho)physiological processes, representing most common targets for pharmacotherapeutic interference. Upon ligand-stimulation the receptors act as guanine nucleotide exchange factors triggering the associated heterotrimeric G-protein to exchange GDP for GTP. This results in dissociation of G-protein subunits enabling GaGTP and Gbg to regulate cellular effectors such as ion channels, transporters and enzymes. Signaling is terminated by the GTPase activity of Ga followed by re-association of G protein subunits which allows subsequent receptor-driven activation/inactivation cycles. G-protein signaling is fine-tuned or modified by various regulators or accessory proteins. These include Regulators of G-protein Signaling (RGS) being responsible for the rapid turnoff of 7TM receptor-dependent pathways. Moreover, Activators of G-protein Signaling (AGS) provide signal input to G proteins in the absence of 7TM receptors or serve as alternative binding partners for G protein subunits. Accumulating evidence suggest that 7TM receptors may also signal in a G-protein-independent manner.

In the canonical pathway, the specificity of the signaling pathway depends on the type of G protein coupled to a specific receptor. In principle, 7TM receptors couple to four subfamilies of G proteins called Gs, Gi/o, Gq and G12/13. We are particularly interested in the function, specificity and biological role of Gi proteins. They belong to the Gi/o subfamily which also comprises neuronally expressed Go proteins, sensory G proteins, i.e. Transducins and Gustducin, and Gz. With the exception of the latter all member share a unique sensitivity towards pertussis toxin. This Bordetella pertussis exotoxin irreversibly modifies the C-terminus of Ga which results in a functional uncoupling of the G-protein from its receptor. We have focused on mutant mouse strains deficient of the three highly-related Gai1-, Gai2- and Gai3-proteins. With this genetic approach we have identified overlapping but also specific roles of these G-protein isoforms in the cardiovascular, endocrine and immunological system. In particular, new and unexpected evidence will be presented on the integration of Gi proteins in cerebro-cardiovascular disorders, diabetes and obesity.

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Selected publications

Grenz A., Nürnberg B., Eltzschig H.K. et al. (2012): Equilibrative nucleoside transporter 1 (ENT1) regulates post-ischemic blood flow during acute kidney injury in mice. J. Clin. Invest. 122, 693-710

Kurig B., Nürnberg B. et al. (2009): Ras is an indispensable coregulator of the class IB phosphoinositide 3-kinase p87/p110?. Proc. Natl. Acad. Sci. USA 106, 20312-20317

Pivarcsi A., Nürnberg B., Homey B. et al. (2007): Tumor immune escape by the loss of homeostatic chemokine expression. Proc. Natl. Acad. Sci. USA 104, 19055-19060

Gohla A., Nürnberg B. et al (2007): An obligatory requirement for the heterotrimeric G protein Gi3 in the anti-autophagic action of insulin in the liver. Proc. Natl. Acad.
Sci. USA 104, 3003-3008

 

Invitant Mireille Montcouquiol (mireille.montcouquiol @ inserm.fr)

Agenda