SGIP1 alters internalization and modulates signaling of activated cannabinoid receptor 1 in a biased manner. (August 2016)

• Record Type: Journal Article
• Authors: Hájková, Alena; Techlovská, Šárka; Dvořáková, Michaela; Chambers, Jayne Nicole; Kumpošt, Jiří; Hubálková, Pavla; Prezeau, Laurent; Blahos, Jaroslav
• Is Part Of: Neuropharmacology. Volume 107(2016)
• Page Start: 201
• Page End: 214
• Publication Date: 2016-08
• Subjects: Seven transmembrane receptors -- G-protein coupled receptors -- Cannabinoid receptor 1 -- Protein-protein interactions -- Bias signaling -- Receptor endocytosis; SGIP1 src homology 3-domain growth factor receptor-bound 2-like (endophilin) interacting protein 1 -- CCP clathrin-coated pit -- AP2 assembly polypeptide 2 -- CB1R cannabinoid receptor 1 -- CME clathrin-mediated endocytosis -- BRET bioluminiscence resonance energy transfer -- CNS central nervous system -- CHAPS 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate -- CRIP1a cannabinoid receptor-interacting protein 1a -- DMSO dimethyl sulfoxide -- Eps15 epidermal growth factor receptor substrate 15 -- ERK 1/2 extracellular signal-regulated kinases1 and 2 -- FBS fetal bovine serum -- FCHo Fer/Cip4 homology only proteins -- FIR fluorescence internalization ratio -- FRET Forster's resonance energy transfer -- GPCRs G-protein coupled receptors -- HEK293 human embryonic kidney 293 -- MC Mander's coefficient -- PC Pearson's coefficient -- PTX Pertussis toxin -- Rluc Renilla luciferase -- Y2H yeast two-hybrid -- YFP yellow fluorescent protein -- WIN WIN 55, 212-2 mesylate, [(3R)-2, 3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1, 2, 3-de]-1, 4-benzoxazin-6-yl]-1-naphthalenyl-methanone, monomethanesulfonate -- AM281 1-(2, 4-Dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide -- CP55940 ((1R, 3R, 4R)-3-[2-hydroxy-4-(1, 1-dimethylheptyl)phenyl]-4-(3- hydroxypropyl)cyclohexan-1-ol) -- ORG27569 (5-chloro-3-ethyl-1H-indole-2-carboxylic acid [2-(4-piperidin-1-yl-phenyl)ethyl]amide); Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2016.03.008
• Languages: English
• ISSNs: 0028-3908

Abstract

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. Graphical abstract: Highlights: We detected SGIP1 as a novel interacting partner of CB1R. SGIP1 interferes with endocytosis of the activated CB1R and stabilizes it on the cell surface. β-arrestin2 association with activated CB1R is enhanced by SGIP1. Certain G-protein signaling activated by CB1R is unaffected by SGIP1, but ERK1/2 pathway is negatively regulated by SGIP1. SGIP1 regulates CB1R signaling in a biased manner.