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Signalling networks associated with 5-HT4 receptors and neurodegenerative disorders

Projects leaders : Aline Dumuis & Sylvie Claeysen

Staff : Maud Cochet, Florence Gaven and Philippe Marin

Collaborations :

 Jeffrey Benovic (T Jefferson University, Philadelphia)
 Evgueni Ponimaskin (Hanover University)
 Monica di Luca (University of Milano)
 Eric Reiter (INRA-University of Tours)

The 5-HT4 receptor is expressed in both peripheral tissues and the central nervous system, where it is involved in cognitive functions, neuroprotection and feeding. Several pro-mnesic 5-HT4 receptor agonists are in clinical development for the treatment of cognitive deficits in Alzheimer’s disease. Our previous studies have revealed that the receptor can initiate G protein-independent signalling mechanisms within a protein complex (“receptosome”). We currently investigate how this receptosome modulates amyloid precursor protein (APP) processing, promoting the non-amyloidogenic pathway (release of soluble extracellular fragment of APP, sAPPα, which exerts neuroprotective effects) and inhibiting the amyloidogenic pathway (formation of Aβ peptide, the major constituent of senile plaques in Alzheimer’s disease patients). Our specific objectives are to determine how 5-HT4 receptors activate the metalloproteinase ADAM10 leading to the formation of sAPPα and how they regulate APP trafficking. Our approach combines biochemistry, proteomics and cellular imaging experiments, using transgenic mice deficient either in 5-HT4 receptors or APP and animal models of Alzheimer’s disease.

Publications related to the project :

Cochet M, Donneger R, Cassier E, Gaven F, Lichtenthaler SF, Marin P, Bockaert J, Dumuis A, Claeysen S. 5-HT4 Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10. ACS Chem. Neurosci. In press.

Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P. (2012) Alzheimer culprits : cellular crossroads and interplay. Cell Signal. 24:1831-40.

Bockaert J., Claeysen S., Compan V. and Dumuis A. (2011) 5-HT(4) receptors, a place in the sun : act two. Curr Opin Pharmacol. 11:87-93.

Pellissier LP, Barthet G, Gaven F, Cassier E, Trinquet E, Pin JP, Marin P, Dumuis A, Bockaert J, Banères JL, Claeysen S. (2011) G Protein Activation by Serotonin Type 4 Receptor Dimers : Evidence That Turning On Two protomers Is More Efficient. J Biol Chem. 286:9985-97.

Barthet G, Carrat G, Cassier E, Barker B, Gaven F, Pillot M, Framery B, Pellissier L, Augier J, Kang DS, Claeysen S, Reiter E, Banères J-L, Benovic JL, Marin P, Bockaert J, Dumuis A (2009) ß-arrestin1 phosphorylation by GRK5 regulates G protein-independent 5-HT4 receptor signalling. EMBO J 28:2706-2718.

Barthet G, Framery B, Gaven F, Pellissier L, Reiter E, Claeysen S, Bockaert J, Dumuis A (2007) 5-hydroxytryptamine 4 receptor activation of the extracellular signal-regulated kinase pathway depends on Src activation but not on G protein or beta-arrestin signaling. Mol Biol Cell 18:1979-1991.

Barthet G, Gaven F, Framery B, Shinjo K, Nakamura T, Claeysen S, Bockaert J, Dumuis A (2005) Uncoupling and endocytosis of 5-hydroxytryptamine 4 receptors. Distinct molecular events with different GRK2 requirements. J Biol Chem 280:27924-27934.

Joubert L, Hanson B, Barthet G, Sebben M, Claeysen S, Hong W, Marin P, Dumuis A, Bockaert J (2004) New sorting nexin (SNX27) and NHERF specifically interact with the 5-HT4a receptor splice variant : roles in receptor targeting. J Cell Sci 117:5367-5379.