A GIPC1-Palmitate Switch Modulates Dopamine Drd3 Receptor Trafficking and Signaling

被引:13
作者
Arango-Lievano, Margarita [1 ,2 ,3 ]
Sensoy, Ozge [4 ]
Borie, Amelie [1 ,2 ,3 ]
Corbani, Maithe [1 ,2 ,3 ]
Guillon, Gilles [1 ,2 ,3 ]
Sokoloff, Pierre [5 ,7 ]
Weinstein, Harel [6 ]
Jeanneteau, Freddy [1 ,2 ,3 ]
机构
[1] Inst Funct Genom, INSERM, U1191, Montpellier, France
[2] CNRS, UMR 5203, Montpellier, France
[3] Univ Montpellier, F-34059 Montpellier, France
[4] Istanbul Medipol Univ, Sch Engn & Nat Sci, Istanbul, Turkey
[5] Ctr Paul Broca, INSERM, U573, Unit Neurobiol & Mol Pharmacol, Paris, France
[6] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA
[7] PSAdvice, Belleserre, France
关键词
ACYL CARRIER PROTEIN; DOMAIN-CONTAINING PROTEIN; D-3; RECEPTOR; MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; BETA(1)-ADRENERGIC RECEPTOR; COUPLED RECEPTORS; FORCE-FIELD; D3; HELIX;
D O I
10.1128/MCB.00916-15
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Palmitoylation is involved in several neuropsychiatric and movement disorders for which a dysfunctional signaling of the dopamine D3 receptor (Drd3) is hypothesized. Computational modeling of Drd3's homologue, Drd2, has shed some light on the putative role of palmitoylation as a reversible switch for dopaminergic receptor signaling. Drd3 is presumed to be palmitoylated, based on sequence homology with Drd2, but the functional attributes afforded by Drd3 palmitoylation have not been studied. Since these receptors are major targets of antipsychotic and anti-Parkinsonian drugs, a better characterization of Drd3 signaling and posttranslational modifications, like palmitoylation, may improve the prospects for drug development. Using molecular dynamics simulations, we evaluated in silico how Drd3 palmitoylation could elicit significant remodeling of the C-terminal cytoplasmic domain to expose docking sites for signaling proteins. We tested this model in cellulo by using the interaction of Drd3 with the G-alpha interacting protein (GAIP) C terminus 1 (GIPC1) as a template. From a series of biochemical studies, live imaging, and analyses of mutant proteins, we propose that Drd3 palmitoylation acts as a molecular switch for Drd3-biased signaling via a GIPC1-dependent route, which is likely to affect the mode of action of antipsychotic drugs.
引用
收藏
页码:1019 / 1031
页数:13
相关论文
共 75 条
[1]   Regulation of Akt signaling by D2 and D3 dopamine receptors in vivo [J].
Beaulieu, Jean-Martin ;
Tirotta, Emanuele ;
Sotnikova, Tatyana D. ;
Masri, Bernard ;
Salahpour, Ali ;
Gainetdinov, Raul R. ;
Borrelli, Emiliana ;
Caron, Marc G. .
JOURNAL OF NEUROSCIENCE, 2007, 27 (04) :881-885
[2]   The Physiology, Signaling, and Pharmacology of Dopamine Receptors [J].
Beaulieu, Jean-Martin ;
Gainetdinov, Raul R. .
PHARMACOLOGICAL REVIEWS, 2011, 63 (01) :182-217
[3]   Lithium antagonizes dopamine-dependent behaviors mediated by an AKT/glycogen synthase kinase 3 signaling cascade [J].
Beaulieu, JM ;
Sotnikova, TD ;
Yao, WD ;
Kockeritz, L ;
Woodgett, JR ;
Gainetdinov, RR ;
Caron, MG .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (14) :5099-5104
[4]   Versatility of Acyl-Acyl Carrier Protein Synthetases [J].
Beld, Joris ;
Finzel, Kara ;
Burkart, Michael D. .
CHEMISTRY & BIOLOGY, 2014, 21 (10) :1293-1299
[5]   MOLECULAR-DYNAMICS WITH COUPLING TO AN EXTERNAL BATH [J].
BERENDSEN, HJC ;
POSTMA, JPM ;
VANGUNSTEREN, WF ;
DINOLA, A ;
HAAK, JR .
JOURNAL OF CHEMICAL PHYSICS, 1984, 81 (08) :3684-3690
[6]   Dopamine receptors and L-dopa-induced dyskinesia [J].
Berthet, Amandine ;
Bezard, Erwan .
PARKINSONISM & RELATED DISORDERS, 2009, 15 :S8-S12
[7]   Attenuation of levodopa-induced dyskinesia by normalizing dopamine D3 receptor function [J].
Bézard, E ;
Ferry, S ;
Mach, U ;
Stark, H ;
Leriche, L ;
Boraud, T ;
Gross, C ;
Sokoloff, P .
NATURE MEDICINE, 2003, 9 (06) :762-767
[8]   Palmitoylation of CCR5 is critical for receptor trafficking and efficient activation of intracellular signaling pathways [J].
Blanpain, C ;
Wittamer, V ;
Vanderwinden, JM ;
Boom, A ;
Renneboog, B ;
Lee, B ;
Le Poul, E ;
El Asmar, L ;
Govaerts, C ;
Vassart, G ;
Doms, RW ;
Parmentier, M .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (26) :23795-23804
[9]   A novel mechanism for regulating transforming growth factor β (TGF-β) signaling -: Functional modulation of type III TGF-β receptor expression through interaction with the PDZ domain protein, GIPC [J].
Blobe, GC ;
Liu, XD ;
Fang, SJJ ;
How, T ;
Lodish, HF .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (43) :39608-39617
[10]   The 'magic tail' of G protein-coupled receptors: an anchorage for functional protein networks [J].
Bockaert, J ;
Marin, P ;
Dumuis, A ;
Fagni, L .
FEBS LETTERS, 2003, 546 (01) :65-72