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Identification of Bip As a CB1 Receptor-Interacting Protein That Fine

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Identification of Bip As a CB1 Receptor-Interacting Protein That Fine Research Articles: Cellular/Molecular Identification of BiP as a CB1 receptor- interacting protein that fine-tunes cannabinoid signaling in the mouse brain https://doi.org/10.1523/JNEUROSCI.0821-21.2021 Cite as: J. Neurosci 2021; 10.1523/JNEUROSCI.0821-21.2021 Received: 15 April 2021 Revised: 22 July 2021 Accepted: 25 July 2021 This Early Release article has been peer-reviewed and accepted, but has not been through the composition and copyediting processes. The final version may differ slightly in style or formatting and will contain links to any extended data. Alerts: Sign up at www.jneurosci.org/alerts to receive customized email alerts when the fully formatted version of this article is published. Copyright © 2021 Costas-Insua et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. 1 Identification of BiP as a CB1 receptor-interacting protein that 2 fine-tunes cannabinoid signaling in the mouse brain 3 4 Abbreviated title: BiP interacts with cannabinoid CB1 receptor 5 6 Carlos Costas-Insua1,2,3, Estefanía Moreno4, Irene B. Maroto1,2,3, Andrea Ruiz-Calvo1,2,3, 7 Raquel Bajo-Grañeras1,2,3, David Martín-Gutiérrez2, Rebeca Diez-Alarcia5,6, 8 M. Teresa Vilaró1,7,8, Roser Cortés1,7,8, Nuria García-Font2,9, Ricardo Martín2,9, 9 Marc Espina1,7,10, Joaquín Botta11, Silvia Ginés1,7,10, Peter J. McCormick11, 10 José Sánchez-Prieto2,9, Ismael Galve-Roperh1,2,3, Guadalupe Mengod1,7,8, 11 Leyre Urigüen5,6, Giovanni Marsicano12, Luigi Bellocchio12, Enric I. Canela1,4, 12 Vicent Casadó4, Ignacio Rodríguez-Crespo1,2,3,*, Manuel Guzmán1,2,3,* 13 14 1Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas 15 (CIBERNED), Madrid 28031, Spain 16 2Department of Biochemistry and Molecular Biology, Instituto Universitario de 17 Investigación Neuroquímica (IUIN), Complutense University, Madrid 28040, Spain 18 3Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid 28034, Spain 19 4Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, Institute of 20 Biomedicine of the University of Barcelona, University of Barcelona, Barcelona 08028, 21 Spain 22 5Department of Pharmacology, University of the Basque Country/Euskal Herriko 23 Unibertsitatea, Leioa 48940, Spain 24 6Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid 25 28029, Spain 1 26 7Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona 08036, 27 Spain 28 8Department of Neurosciences and Experimental Therapeutics, Institut d’ Investigacions 29 Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas, Barcelona 30 08036, Spain 31 9Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid 32 28040, Spain 33 10Department of Biomedicine, School of Medicine, Institute of Neuroscience, University 34 of Barcelona, Barcelona 08036, Spain 35 11Centre for Endocrinology, William Harvey Research Institute, Barts and The London 36 School of Medicine and Dentistry, Queen Mary University of London, EC1M 6BQ 37 London, United Kingdom 38 12Institut National de la Santé et de la Recherche Médicale (INSERM) and University of 39 Bordeaux, NeuroCentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, 40 Bordeaux 33077, France 41 42 Correspondence: Manuel Guzmán ([email protected]), Ignacio Rodríguez- 43 Crespo ([email protected]) 44 45 Number of pages: 58 46 Number of figures, tables, multimedia, and 3D models: 10 figures, 2 tables, 0 47 multimedia, 0 3D models 48 Number of words for abstract, introduction, and discussion: 210 abstract, 583 49 introduction, 682 discussion 50 2 51 Conflict of interest statement 52 The authors declare no competing financial interests. 53 54 Acknowledgments 55 This work was supported by the Spanish Ministerio de Ciencia e Innovación 56 (MICINN/FEDER; grants RTI2018-095311-B-I00 to MG, SAF-2017-87629-R to EIC and 57 VC, PID2019-106404RB-I00 to LU, BFU 2017-83292-R to JS-P, and RTI2018-094374- 58 B-I00 to SG), Centro de Investigación Biomédica en Red sobre Enfermedades 59 Neurodegenerativas (CIBERNED/ISCIII; grant PI2018/01 to MG, SG, and GMe), and UK 60 Research and Innovation Biotechnology and Biological Sciences Research Council 61 (grant BB/R006946/1 to PJM). LB and GM were supported by INSERM. CC-I and IBM 62 were supported by contracts from the Spanish Ministerio de Universidades (Formación 63 de Profesorado Universitario Program, references FPU16/02593 and FPU15/01833, 64 respectively). RB-G was supported by a contract from the Spanish Ministerio de Ciencia 65 e Innovación (MICINN/FEDER; Juan de la Cierva Program). We are indebted to Lucía 66 Rivera, Elena García-Taboada, Carlos Montero, Andrea Macías, Alicia Álvaro, Guillermo 67 Martín-Migallón, and Susana Muñoz-Morales for expert laboratory assistance. 68 3 69 Abstract 70 Cannabinoids, the bioactive constituents of cannabis, exert a wide array of effects on the 71 brain by engaging type-1 cannabinoid receptor (CB1R). Accruing evidence supports that 72 cannabinoid action relies on context-dependent factors such as the biological 73 characteristics of the target cell, suggesting that cell population-intrinsic molecular cues 74 modulate CB1R-dependent signaling. Here, by using a yeast two-hybrid-based high- 75 throughput screening, we identified BiP as a potential CB1R-interacting protein. We next 76 found that CB1R and BiP interact specifically in vitro, and mapped the interaction site 77 within the CB1R C-terminal (intracellular) domain and the BiP C-terminal (substrate- 78 binding) domain-α. BiP selectively shaped agonist-evoked CB1R signaling by blocking 79 an “alternative” Gq/11 protein-dependent signaling module, while leaving the “classical” 80 Gi/o protein-dependent inhibition of the cAMP pathway unaffected. In situ proximity 81 ligation assays conducted on brain samples from various genetic mouse models of 82 conditional loss or gain of CB1R expression allowed to map CB1R-BiP complexes 83 selectively on terminals of GABAergic neurons. Behavioral studies using cannabinoid- 84 treated male BiP+/- mice supported that CB1R-BiP complexes modulate cannabinoid- 85 evoked anxiety, one of the most frequent undesired effects of cannabis. Altogether, by 86 identifying BiP as a CB1R-interacting protein that controls receptor function in a 87 signaling pathway- and neuron population-selective manner, our findings may help to 88 understand the striking context-dependent actions of cannabis in the brain. 89 4 90 Significance Statement 91 Cannabis use is increasing worldwide, so innovative studies aimed to understand its complex 92 mechanism of neurobiological action are warranted. Here, we found that cannabinoid CB1 93 receptor (CB1R), the primary molecular target of the bioactive constituents of cannabis, 94 interacts specifically with an intracellular protein called BiP. The interaction between CB1R 95 and BiP occurs selectively on terminals of GABAergic (inhibitory) neurons, and induces a 96 remarkable shift in the CB1R-associated signaling profile. Behavioral studies conducted in 97 mice support that CB1R-BiP complexes act as fine-tuners of anxiety, one of the most frequent 98 undesired effects of cannabis use. Our findings open a new conceptual framework to 99 understand the striking context-dependent pharmacological actions of cannabis in the brain. 100 5 101 Introduction 102 Preparations of the hemp plant Cannabis sativa L. have been used by humankind for 103 millennia. During the last decades there has been a strong renaissance in the study of 104 the molecular and pharmacological bases of cannabinoid action, and, in concert, many 105 countries have approved the use of cannabinoid-based medicines and standardized 106 preparations of medicinal cannabis (Hill, 2015; Abrams, 2018). Both the therapeutic and 107 the adverse effects of cannabis are mostly attributed to a single molecule, ∆9- 108 tetrahydrocannabinol (THC) (Mechoulam et al., 2014). This compound engages and 109 activates two specific G protein-coupled receptors (GPCRs), designated as cannabinoid 110 CB1 receptor (CB1R) and cannabinoid CB2 receptor (CB2R) (Pertwee et al., 2010). 111 CB1R is one of the most abundant GPCRs in the mammalian brain (Katona and Freund, 112 2008; Pertwee et al., 2010; Dudok et al., 2015). It mediates a large number of 113 pharmacological effects of THC, and, upon binding endocannabinoids (anandamide and 114 2-arachidonoylglycerol), participates in the physiological control of multiple processes 115 such as motor behavior, learning and memory, fear and anxiety, pain, food intake, and 116 energy metabolism (Piomelli, 2003; Mechoulam et al., 2014). 117 The precise molecular mechanism of CB1R action remains unsolved. For 118 example, CB1R couples to the inhibitory family of heterotrimeric G proteins (Gi/o), but its 119 expression and signaling efficacy differs remarkably between excitatory and inhibitory 120 neurons (Steindel et al., 2013), which could explain, at least in part, the widely reported 121 biphasic effects elicited by THC and other CB1R agonists (Bellocchio et al., 2010; Rey et 122 al., 2012; Mechoulam and Parker, 2013). Likewise, under different cellular settings, 123 CB1R can signal through other G protein families as Gq/11 and Gs (Lauckner et al., 2005; 124 Priestley et al., 2017). Furthermore, CB1R activation protects neurons from death in a 125 wide array of pathological
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