title: SGIP1 alters internalization and modulates signaling of activated cannabinoid receptor 1 in a biased manner.
abstract: Many diseases of the nervous system are accompanied by alterations in synaptic functions. Synaptic plasticity mediated by the endogenous cannabinoid system involves the activation of the cannabinoid receptor 1 (CB1R). The principles of CB1R signaling must be understood in detail for its therapeutic exploration. We detected the Src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 (SGIP1) as a novel CB1R partner. SGIP1 is functionally linked to clathrin-mediated endocytosis and its overexpression in animals leads to an energy regulation imbalance resulting in obesity. We report that SGIP1 prevents the endocytosis of activated CB1R and that it alters signaling via the CB1R in a biased manner. CB1R mediated G-protein activation is selectively influenced by SGIP1, β-arrestin associated signaling is changed profoundly, most likely as a consequence of the prevention of the receptor's internalization elicited by SGIP1.
authors.affiliation: Institute of Molecular Genetics, Academy of Science of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Alena
authors.initials: A
authors.lastname: Hájková
authors.affiliation: Institute of Molecular Genetics, Academy of Science of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Šárka
authors.initials: Š
authors.lastname: Techlovská
authors.affiliation: Institute of Molecular Genetics, Academy of Science of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Dvořáková
authors.affiliation: Institute of Molecular Genetics, Academy of Science of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Jayne Nicole
authors.initials: JN
authors.lastname: Chambers
authors.affiliation: Institute of Molecular Genetics, Academy of Science of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Kumpošt
authors.affiliation: Institute of Molecular Genetics, Academy of Science of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic.
authors.forename: Pavla
authors.initials: P
authors.lastname: Hubálková
authors.affiliation: Institut de Génomique Fonctionnelle, University of Montpellier 1 and 2, Montpellier, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Prezeau
authors.affiliation: Institute of Molecular Genetics, Academy of Science of the Czech Republic, Videnska 1083, 14220 Prague 4, Czech Republic. Electronic address: blahos@img.cas.cz.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Blahos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001921:Brain / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000378:metabolism; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D012441:Saccharomyces cerevisiae; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000071560:beta-Arrestin 2 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D043884:Receptor, Cannabinoid, CB1; C000620623:SGIP1 protein, mouse; D000071560:beta-Arrestin 2
keywords: Bias signaling; Cannabinoid receptor 1; G-protein coupled receptors; Protein-protein interactions; Receptor endocytosis; Seven transmembrane receptors