Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling. Export

@article{citeulike:2795400, abstract = {Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through beta-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human beta-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying beta-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating beta-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced beta-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating beta-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling.}, address = {H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark; Molecular Neuropharmacology Group, Department of Neuroscience and Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3C, 2200 Copenhagen, Denmark.}, author = {Klewe, Ib V V. and Nielsen, S{\o}ren M M. and Tarp{\o}, Louise and Urizar, Eneko and Dipace, Concetta and Javitch, Jonathan A A. and Gether, Ulrik and Egebjerg, Jan and Christensen, Kenneth V V.}, citeulike-article-id = {2795400}, citeulike-linkout-0 = {http://dx.doi.org/10.1016/j.neuropharm.2008.03.015}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/18455202}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=18455202}, day = {8}, doi = {10.1016/j.neuropharm.2008.03.015}, issn = {0028-3908}, journal = {Neuropharmacology}, keywords = {activation, active-state, agonist, arrestin, biased\_agonism, binding, disease, fluorescence, imaging, internalization, pharmacology}, month = {April}, posted-at = {2008-05-13 16:24:49}, priority = {2}, title = {Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling.}, url = {http://dx.doi.org/10.1016/j.neuropharm.2008.03.015}, year = {2008} }

TY - JOUR ID - citeulike:2795400 L3 - citeulike-article-id:2795400 N2 - Drugs acting at dopamine D2-like receptors play a pivotal role in the treatment of both schizophrenia and Parkinson's disease. Recent studies have demonstrated a role for G-protein independent D2 receptor signaling pathways acting through beta-arrestin. In this study we describe the establishment of a Bioluminescence Resonance Energy Transfer (BRET) assay for measuring dopamine induced recruitment of human beta-arrestin2 to the human dopamine D2 receptor. Dopamine, as well as the dopamine receptor agonists pramipexole and quinpirole, acted as full agonists in the assay as reflected by their ability to elicit marked concentration dependent increases in the BRET signal signifying beta-arrestin2 recruitment to the D2 receptor. As expected from their effect on G-protein coupling and cAMP levels mediated through the D2 receptor RNPA, pergolide, apomorphine, ropinirole, bromocriptine, 3PPP, terguride, aripiprazole, SNPA all acted as partial agonists with decreasing efficacy in the BRET assay. In contrast, a wide selection of typical and atypical anti-psychotics was incapable of stimulating beta-arrestin2 recruitment to the D2 receptor. Moreover, we observed that haloperidol, sertindole, olanzapine, clozapine and ziprasidone all fully inhibited the dopamine induced beta-arrestin2 recruitment to D2 receptor (short variant) in a concentration dependent manner. We conclude that most anti-psychotics are incapable of stimulating beta-arrestin2 recruitment to the dopamine D2 receptor, in accordance with their antagonistic properties at the level of G-protein coupling. JF - Neuropharmacology SN - 0028-3908 AD - H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark; Molecular Neuropharmacology Group, Department of Neuroscience and Pharmacology, The Panum Institute, University of Copenhagen, Blegdamsvej 3C, 2200 Copenhagen, Denmark. TI - Recruitment of beta-arrestin2 to the dopamine D2 receptor: Insights into anti-psychotic and anti-parkinsonian drug receptor signaling. KW - activation KW - active-state KW - agonist KW - arrestin KW - biased_agonism KW - binding KW - disease KW - fluorescence KW - imaging KW - internalization KW - pharmacology AU - Klewe, Ib V AU - Nielsen, Søren M AU - Tarpø, Louise AU - Urizar, Eneko AU - Dipace, Concetta AU - Javitch, Jonathan A AU - Gether, Ulrik AU - Egebjerg, Jan AU - Christensen, Kenneth V PY - 2008/04/08/ UR - http://dx.doi.org/10.1016/j.neuropharm.2008.03.015 ER -