Endogenous vs Exogenous Allosteric Modulators in GPCRs: A dispute for shuttling CB1 among different membrane microenvironments.
A Cannabinoid Receptor 1 (CB1) binding site for the selective allosteric modulator ORG27569 is here identified through an integrate approach of consensus pocket prediction, mutagenesis studies and Mass Spectrometry. This unprecedented ORG27569 pocket presents the structural features of a Cholesterol Consensus Motif, a cholesterol interacting region already found in other GPCRs. ORG27569 and cholesterol affects oppositely CB1 affinity for orthosteric ligands. Moreover, the rise in cholesterol intracellular level results in CB1 trafficking to the axonal region of neuronal cells, while, on the contrary, ORG27568 binding induces CB1 enrichment at the soma. This control of receptor migration among functionally different membrane regions of the cell further contributes to downstream signalling and adds a previously unknown mechanism underpinning CB1 modulation by ORG27569 , that goes beyond a mere control of receptor affinity for orthosteric ligands.
Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.
Mariano
M
Stornaiuolo
Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.
Agostino
A
Bruno
Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.
Lorenzo
L
Botta
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Giuseppe
G
La Regina
DiSTABiF, Seconda Università di Napoli, Via Vivaldi 43, 81100 Caserta, Italy.
Sandro
S
Cosconati
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, Piazzale Aldo Moro 5, I-00185 Roma, Italy.
Romano
R
Silvestri
Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.
Luciana
L
Marinelli
Department of Pharmacy, University of Naples "Federico II", via D. Montesano 49, 80131 Naples, Italy.
Ettore
E
Novellino
D000494:Allosteric Regulation; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D042541:Intracellular Space / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D021381:Protein Transport; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
C572504:5-chloro-3-ethyl-1H-indole-2-carboxylic acid (2-(4-piperidin-1-yl-phenyl)ethyl)amide; D007211:Indoles; D008024:Ligands; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1; D043562:Receptors, G-Protein-Coupled; D002784:Cholesterol