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The Multiple Waves of Cannabinoid 1 Receptor Signaling

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The Multiple Waves of Cannabinoid 1 Receptor Signaling 1521-0111/90/5/620–626$25.00 http://dx.doi.org/10.1124/mol.116.104539 MOLECULAR PHARMACOLOGY Mol Pharmacol 90:620–626, November 2016 Copyright ª 2016 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license http://creativecommons.org/licenses/by-nc/4.0/. MINIREVIEW—A LATIN AMERICAN PERSPECTIVE ON G PROTEIN-COUPLED RECEPTORS The Multiple Waves of Cannabinoid 1 Receptor Signaling Carlos Nogueras-Ortiz and Guillermo A. Yudowski Institute of Neurobiology(C.N.-O., G.A.Y.) and Department of Anatomy and Neurobiology (G.A.Y.), University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico Received April 1, 2016; accepted June 22, 2016 Downloaded from ABSTRACT The cannabinoid 1 receptor (CB1R) is one of the most abundant underlying molecular mechanisms and physiologic impacts of G protein–coupled receptors (GPCRs) in the central nervous these waves. Simultaneously, it provides new opportunities to system, with key roles during neurotransmitter release and harness the therapeutic potential of the cannabinoid system and molpharm.aspetjournals.org synaptic plasticity. Upon ligand activation, CB1Rs may signal other GPCRs. Over the last several years, we have significantly in three different spatiotemporal waves. The first wave, which is expanded our understanding of the mechanisms and pathways transient (,10 minutes) and initiated by heterotrimeric G pro- downstream from the CB1R. The identification of receptor teins, is followed by a second wave (.5 minutes) that is mediated mutations that can bias signaling to specific pathways and the by b-arrestins. The third and final wave occurs at intracellular use of siRNA technology have been key tools to identifying which compartments and could be elicited by G proteins or b-arrestins. signaling cascades are controlled by G proteins or b-arrestins. This complexity presents multiple challenges, including the Here, we review our current knowledge on CB1R signaling, with correct classification of receptor ligands, the identification of particular emphasis on the mechanisms and cascades mediated the signaling pathways regulated by each wave, and the by b-arrestins downstream from the CB1R. at ASPET Journals on September 28, 2021 Introduction pathways and molecular mechanisms underlying functional selectivity. With the ability to specifically abrogate desired Functional selectivity, also called ligand or receptor bias, is proteins, either genetically or chemically, while analyzing the ability of ligands to activate a subset of the full repertoire downstream effectors, our current knowledge of these events of signaling cascades available to individual G protein– has increased exponentially; however, we are still far from coupled receptors (GPCRs) (Urban et al., 2007). This concept, having a complete picture of the events that follow GPCR based on numerous analytical observations from different laboratories, challenged our classic definition of a ligand’s activation that lead to biologic responses. Assisted by the intrinsic efficacy (i.e., the property of a ligand/receptor pair to development of powerful computational tools for structure/- elicit the full set of biologic responses). Functional selectivity function analysis, additional relevant pieces of this intricate also provided a novel conceptual framework and therapeutic jigsaw puzzle are realized almost daily with the continuous opportunities to pharmacologically control GPCR function description of GPCR crystal structures and their associated (Ariens, 1954; Kenakin, 2004), which resulted in the realiza- proteins (Katritch et al., 2013; Maudsley et al., 2013; Johnston tion that signaling from individual GPCRs is even more and Filizola, 2014; Shukla et al., 2014a). complex than initially proposed and that receptor signaling In this review, we discuss functional selectivity of the is in fact pluridimensional (Galandrin et al., 2007; Kenakin, cannabinoid 1 receptor (CB1R), one of the most highly 2011; Luttrell, 2014). Elucidation of GPCR pluridimension- expressed GPCRs in the central nervous system. First, we ality has led to the rational search for more effective thera- review the different signaling waves characterizing functional peutic agents and the systematic exploration of the signaling selectivity of the CB1R that are mediated by G proteins and b-arrestins. Then we focus the discussion on ligand bias This work was supported by the following research grants from the National toward b-arrestins and the underlying molecular mecha- Institutes of Health to G.A.Y. and C.N.O. [Grants DA023444 and nisms. We discuss the in vivo data from wild-type, knockout, R01DA037924]; G.A.Y and F.D.P. G.A.Y received further support from the Puerto Rico Science Trust. and knock-in mice and conclude by highlighting intriguing dx.doi.org/10.1124/mol.116.104539. problems and suggesting areas where further research is ABBREVIATIONS: AEA, anandamide; CB1R, cannabinoid 1 receptor; CP, CP55,940; CREB, cAMP response element–binding protein; Δ9-THC, Δ9-tetrahydrocannabinol; ERK1/2, extracellular signal-regulated protein kinases 1 and 2; GPCRs, G protein–coupled receptors; GRK, G protein– coupled receptor kinases; JNK, c-Jun N-terminal kinase; p38a, mitogen-activated protein kinase 14; PTX, pertussis toxin; Src, SRC proto- oncogene, nonreceptor tyrosine kinase; 2-AG, 2-arachidonoylglycerol; WIN, WIN55,212-2. 620 b-Arrestin–Mediated Signaling from Cannabinoid 1 Receptor 621 needed to understand the physiologic roles and therapeutic membrane, signaling from intracellular native receptors was potential of b-arrestin–mediated signaling of the CB1R. shown to stimulate extracellular signal-regulated protein The CB1R is one of the most abundant GPCRs in the central kinase (ERK) phosphorylation in Neuro2A cells. Indirect nervous system, with expression levels ranging between 0.5 support of intracellular signaling was further presented by and 7 pmol/mg protein in numerous areas of the rat brain coimmunoprecipitation of G proteins and CB1Rs from endo- (Herkenham et al., 1991; Mackie, 2008; Marsicano and Kuner, somal compartments isolated from these cells (Rozenfeld and 2008). CB1R localization in neuronal cells is highly polarized Devi, 2008). More recently, calcium release from intracellular to axons and presynaptic sites, where they control synaptic stores was demonstrated by injecting ananadamide into neurotransmitter release and neuronal function (Howlett human embryonic kidney cells transfected with CB1Rs, et al., 1990; Mackie, 2008; Castillo et al., 2012). They are further suggesting a signaling wave from receptors localized activated by their endogenous ligands (endocannabinoids), in intracellular compartments (Brailoiu et al., 2011). Careful such as anandamide and 2-arachidonyl glycerol (2-AG), and consideration should be taken, however, when analyzing they are also activated by tetrahydrocannabinol (D9-THC), the receptor signaling and trafficking, particularly when compar- main psychoactive ingredient in marijuana, that has been ing heterologous systems, different cellular models, and linked to multiple physiopathological conditions. The phar- ligands at saturating or high concentrations. When trying to macologic regulation of the CB1R has been proposed as a understand receptor function, factors that should be taken therapeutic strategy for many neuropsychiatric disorders into consideration include differences in receptor and acces- Downloaded from ranging from anxiety and stress to neurodegenerative disease sory protein expression levels, their cellular localization, and epilepsy (Howlett et al., 2002; Howlett, 2005; Mackie, ligand bias, and ligand on/off rates among others. 2006; Lutz et al., 2015). Are these signaling waves relevant in vivo? What are their possible biologic roles? Are they present in some, but not all, cells? We are at the beginning of a new era of GPCR pharma- CB Receptor Signals in Three Different Waves molpharm.aspetjournals.org 1 cology, and these questions must be addressed to help the Biochemical analysis indicates that CB1Rs, like multiple rational design of new and improved therapeutics. other GPCRs, such as angiotensin type 1 receptor and type 1 parathyroid hormone-related protein receptor, can signal in Multifaceted b-Arrestins three distinct spatiotemporal waves (Luttrell and Gesty-Palmer, 2010; Lohse and Calebiro, 2013). An initial wave mediated by Four highly homologous b-arrestin isoforms have been heterotrimeric Gai/o proteins begins after ligands bind receptors described in mammals. Arrestin 1 and arrestin 4 (visual at the plasma membrane, leading to a rapid decrease in cAMP arrestins) are expressed only in the retina, and arrestin levels, a decrease in Ca21 conductance, and an increase in K1 2 and 3 (referred in this review as b-arrestin 1 and b-arrestin conductance (Fig. 1) (Howlett et al., 2004). CB1Rs present 2, respectively) are expressed ubiquitously (Gainetdinov et al., at ASPET Journals on September 28, 2021 significant functional selectivity at the G protein level. CB1Rs 2004; Gurevich and Gurevich, 2006; Premont and Gainetdinov, couple mainly to heterotrimeric Gi/o butalsotootherGproteins 2007). b-arrestins were initially identified in the late 1980s (Glass and Northup, 1999; Varga et al., 2008; Bosier et al., 2010). and early 1990s as key proteins during the inactivation or This promiscuity has been extensively characterized utilizing “arrest” of ligand activated GPCRs (Pfister et al., 1985; in vitro assays in different cell lines, further emphasizing
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