G-protein-coupled receptor kinases (GRKs) and arrestins in cardiovascular function and disease

• Forschungsstelle: EU FRP
• Projektnummer: 97.0523
• Projekttitel Englisch: G-protein-coupled receptor kinases (GRKs) and arrestins in cardiovascular function and disease

Schlüsselwörter (Englisch)

G protein-coupled receptor kinases; arrestin; desensitization; adrenergic receptors; G protein-coupled receptors

Alternative Projektnummern (Englisch)

EU project number: BMH4CT983566

Forschungsprogramme (Englisch)

EU-programme: 4. Frame Research Programme - 4.2 Agriculture and agroindustry

Kurzbeschreibung (Englisch)

See abstract

Weitere Hinweise und Angaben (Englisch)

Full name of research-institution/enterprise:
Université de Lausanne
Institut de Pharmacologie et de Toxicologie

Partner und Internationale Organisationen (Englisch)

Universidad de Madrid (E), Universität Würzburg (D), Istituto M. Negri (I)

Abstract (Englisch)

In the last year of funding, our research focussed on two main areas of investigation that are distinct, but both complementary to the interests of the other groups participating to the project.
1) Molecular mechanisms of (1-AR function. Recently, most of our effort has been devoted to the interpretation of several new and old mutagenesis results in the context of a new homology model of the (1b-AR based on the recently solved crystal structure of rhodopsin (Greasley et al., in press). The results of this work highlighted the crucial role of the helix3/helix 6 interface in receptor activation. The new receptor model will represent a more general model applicable to other GPCRs investigated in the context of this collaborative project.
2) The role of the (1-AR subtypes in the cardiovascular system We had previously reported that this receptor subtype contributes to mediate the blood pressure response induced by catecholamines. These results have been confirmed in a collaborative work by Nivoit et al. (in press) that reported also that the elastic properties of the aortic wall in the knock out mice were normal. As a result of the collaboration with Prof. Paul Simpson at UCSF and Prof. G. Tsujimoto at the University of Tokyo, knock out models lacking both the (1a and (1b ((1a/b KO) or both the (1d and (1b ((1d/b KO) have been created. Whereas cardiac development has not changed in mice lacking either the (1a or (1b-AR subtype, the (1a/b KO mice display significantly reduced heart growth and decreased cardiac function by echocardiography (O'Connell et al., in press). Whereas the basal blood pressure and heart rate are normal in lacking either the (1a or (1d-AR subtype, they are significantly reduced in the (1d/b KO mice (manuscript in preparation). Altogether, these findings highlight that whereas both the (1a and (1b-AR subtypes play a role in cardiac growth, the (1a and (1b-AR, but not the (1a, are involved in the regulation of blood pressure. The systematic comparison among the different KO models created will finally allow to significantly advance our knowledge on the role of distinct AR subtypes in the regulation of the cardiovascular function. Despite the fact that the EU project was mainly focussed on the cardiovascular system, we extended our study to investigate the role of the (1b-AR in the regulation of glucose homeostasis. Interestingly, we have found that the (1b-AR is involved in the mechanisms underlying insulin and leptin secretion as well as in the sensitivity to these hormones (Burcelin et al., manuscript in preparation).

Datenbankreferenzen (Englisch)

Swiss Database: Euro-DB of the
State Secretariat for Education and Research
Hallwylstrasse 4
CH-3003 Berne, Switzerland
Tel. [phone]
Swiss Project-Number: 97.0523