Receptor desensitization is at the origin nf the progressive reduction of efficacy of some drug treatment. Adrenergic (beta2 and alpha2), muscarinic cholinergic, serotonergic (5-HT4) and many other G-protein coupled receptors (GR) are rapidly desensitized when stimulated by an agonist. G-protein coupled receptor kinases (GRK) and beta-arrestins are two families of proteins that are responsible for this process. Despite a better understanding of the molecular mechanisms involving
GRK/beta-arrestins little attention has been paid to the functional roles of these latter proteins.
The aim of our project is to investigates in some rat brain regions, the adaptative changes in GRK/beta-arrestins expression (mRNA and proteins) and activity followlng repeated antidepressant treatment (noradrenergic and serotonergic uptake inhibitor) or specific neural lesion (with 5,7-DHT or DSP-4 neurotoxins). In situ hybridization; Northern blot, rhodopsin phosphorylation assay and quantitative autoradiogaphy shall be used. GRK/,beta-arrestins-induced desensitization could become a new pharmacological targets.