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The Serine Hydrolases MAGL, ABHD6 and ABHD12 As Guardians of 2-Arachidonoylglycerol Signalling Through Can- Nabinoid Receptors

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The Serine Hydrolases MAGL, ABHD6 and ABHD12 As Guardians of 2-Arachidonoylglycerol Signalling Through Can- Nabinoid Receptors Acta Physiol 2012, 204, 267–276 REVIEW The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through can- nabinoid receptors J. R. Savinainen, S. M. Saario and J. T. Laitinen School of Medicine, Institute of Biomedicine/Physiology, University of Eastern Finland (UEF), Kuopio, Finland Received 25 February 2011, Abstract revision requested 10 March 2011, The endocannabinoid 2-arachidonoylglycerol (2-AG) is a lipid mediator revision received 11 March 2011, involved in various physiological processes. In response to neural activity, accepted 12 March 2011 Correspondence: J. T. Laitinen, 2-AG is synthesized post-synaptically, then activates pre-synaptic cannabinoid PhD, School of Medicine, Institute CB1 receptors (CB1Rs) in a retrograde manner, resulting in transient and long- of Biomedicine/Physiology, lasting reduction of neurotransmitter release. The signalling competence of University of Eastern Finland 2-AG is tightly regulated by the balanced action between ‘on demand’ bio- (UEF), POB 1627, FI-70211 synthesis and degradation. We review recent research on monoacylglycerol Kuopio, Finland. lipase (MAGL), ABHD6 and ABHD12, three serine hydrolases that together E-mail: jarmo.laitinen@uef.fi account for approx. 99% of brain 2-AG hydrolase activity. MAGL is Re-use of this article is permitted responsible for approx. 85% of 2-AG hydrolysis and colocalizes with CB1R in in accordance with the Terms and axon terminals. It is therefore ideally positioned to terminate 2-AG-CB1R Conditions set out at http://wiley signalling regardless of the source of this endocannabinoid. Its acute phar- onlinelibrary.com/onlineopen# macological inhibition leads to 2-AG accumulation and CB1R-mediated OnlineOpen_Terms behavioural responses. Chronic MAGL inactivation results in 2-AG overload, desensitization of CB1R signalling and behavioural tolerance. ABHD6 accounts for approx. 4% of brain 2-AG hydrolase activity but in neurones it rivals MAGL in efficacy. Neuronal ABHD6 resides post-synaptically, often juxtaposed with CB1Rs, and its acute inhibition leads to activity-dependent accumulation of 2-AG. In cortical slices, selective ABHD6 blockade facilitates CB1R-dependent long-term synaptic depression. ABHD6 is therefore posi- tioned to guard intracellular pools of 2-AG at the site of generation. ABHD12 is highly expressed in microglia and accounts for approx. 9% of total brain 2-AG hydrolysis. Mutations in ABHD12 gene are causally linked to a neurodegen- erative disease called PHARC. Whether ABHD12 qualifies as a bona fide member to the endocannabinoid system remains to be established. Keywords 2-AG hydrolase, ABHD12, ABHD6, endocannabinoid, monoa- cylglycerol lipase, a/b-hydrolase domain. Lipid molecules not only serve as building blocks of the brain tissue is enriched in polyunsaturated fatty acids central nervous system (CNS) but are being increasingly (PUFAs), in particular arachidonic acid (AA, 20:4n-6) appreciated as physiological mediators of signal trans- and docosahexanoid acid (DHA, 22:6n-3). These long- duction. Molecular components of the lipid signalling chain PUFAs are needed for normal brain development machineries show promise as therapeutic targets for and function. Endocannabinoids are endogenous various diseases. In contrast with peripheral tissues, AA-containing lipid mediators involved in the regula- Ó 2011 The Authors Acta Physiologica Ó 2011 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2011.02280.x 267 The three guardians of 2-AG signalling Æ J R Savinainen et al. Acta Physiol 2012, 204, 267–276 tion of various physiological and pathophysiological ical regulation of the level and signalling competence of processes, including neurotransmission, mood, appetite, 2-AG through the CBRs. The focus will be on MAGL, nociception, addiction, inflammation, peripheral metab- ABHD6 and ABHD12, the three serine hydrolases that olism and reproduction (Freund et al. 2003, Piomelli together account for approx. 99% of 2-AG hydrolysis 2003, Di Marzo et al. 2007, Kano et al. 2009). The eCB in the CNS. system consists of two G protein-coupled cannabinoid receptors (CB1R and CB2R), their endogenous activat- Physiology and logic of the eCB system in the ing ligands (the eCBs), as well as enzymes involved in CNS the biosynthesis and inactivation of these ligands. The two well-characterized eCBs, N-arachidonoylethanol- The discovery of CBRs and their endogenous ligands amine (anandamide, AEA) and 2-arachidonoylglycerol has greatly accelerated research on cannabinoid actions (2-AG), bind to and activate both CB1R and CB2R with in the brain. Indeed, CB1R is among the most abun- somewhat distinct potencies and efficacies. When tested dantly expressed and widely distributed GPCR in the under comparable assay conditions, 2-AG is more brain (Herkenham et al. 1991) (Fig. 1). CB1R unlikely potent than AEA and behaves a full agonist at both evolved merely to mediate the ‘bliss’ attributed to receptor subtypes (Sugiura et al. 2006). In addition, delta9-tetrahydrocannabinol (THC), the major psycho- AEA can activate the vanilloid receptor TRPV1, a active component of Cannabis sativa, nor does nature member of the transient receptor potential family maintain protein synthesis just for reserve. Instead, the of cation channels that mediates pain sensation abundance of CB1R in specific types of neurones and its (De Petrocellis & Di Marzo 2009). Besides CB1R and enrichment into pre-synaptic terminals throughout the CB2R, an orphan G protein-coupled receptor (GPCR), brain strongly suggests that CB1R evolved specifically termed GPR55, has been identified and often referred to to mediate eCB signalling. It is now well established as the third putative (or atypical) cannabinoid receptor. that in response to neural activity, eCBs are produced However, the pharmacology of this receptor is still ‘on demand’ and released from post-synaptic neurones, controversial and an increasing body of evidence then activate pre-synaptic CB1Rs in a retrograde suggests that the non-cannabinoid lipid lysophosphat- manner, resulting in transient and long-lasting reduc- idylinositol, rather than AEA or 2-AG, acts as the tion of neurotransmitter release at various central cognate agonist of this receptor (Pertwee et al. 2010). synapses (Alger 2002, Freund et al. 2003, Piomelli The purpose of this review is to cover recent research 2003, Kano et al. 2009). Such a retrograde signalling that has advanced our understanding on the physiolog- mode has established a new concept how diffusible lipid Figure 1 Functional autoradiography reveals wide distribution of CB1R-Gi signalling axis in the central nervous system. The method utilizes the radio-labelled GTP analogue [35S]GTPcS that incorporates into activated heterotrimeric G proteins in cell membrane following stimulation of Gi-coupled receptors, either with exogenous or endogenous agonists (Laitinen 2004). The image on the left depicts basal G protein activity in the absence of added agonists and with tonic adenosine A1 receptor signal occluded. In the middle panel, CB1Rs were stimulated using the potent synthetic cannabinoid agonist CP55,940. The brain regions with activation of CB1R-Gi axis include the caudate putamen (Cpu), the cerebral cortex (Cx), the hippocampus (Hi), and the molecular layer of cerebellum (Cbm), closely matching CB1R distribution pattern obtained by classical receptor autoradiography (Herkenham et al. 1991). In the panel at right, pre-treatment of brain sections with the broad spectrum irreversibly acting serine hydrolase inhibitor methylarachidonylfluorophosphonate (MAFP) results in endogenous 2-arachidonoylglycerol (AG) accumulation and 2-AG-dependent CB1R activity throughout the CB1R-responsive brain regions. Previous studies (Paloma¨ki et al. 2007) have demonstrated that (1) the responses to CP55,940 and MAFP are fully blocked by the CB1R-selective antagonist AM251, (2) the MAFP response is not mimicked by selective inhibitor of fatty acid amide hydrolase, ruling our any contribution of AEA, (3) MAFP does not directly activate CB1Rs and 4) MS–GC analysis indicated elevated 2-AG levels in MAFP-treated sections. Ó 2011 The Authors 268 Acta Physiologica Ó 2011 Scandinavian Physiological Society, doi: 10.1111/j.1748-1716.2011.02280.x Acta Physiol 2012, 204, 267–276 J R Savinainen et al. Æ The three guardians of 2-AG signalling messengers, by encaging their cognate GPCRs, can Activity-dependent cleavage of membrane provide both short- and long-term fine-tuning of phospholipids for retrograde eCB-GPCR synaptic efficacy and neural activity. Electrophysiolo- signalling gists have found robust modulation of synaptic plastic- ity and thus introduced new terminology, such as Biosynthesis and release of 2-AG can be induced by depolarization-induced suppression of excitation either depolarization or activation of Gq-coupled (DSE), and depolarization-induced suppression of inhi- GPCRs, typically group I metabotropic glutamate bition (DSI), both of which are best explained by short- receptors (mGluR1 or mGluR5) or M1/M3 muscarinic term retrograde eCB signalling inhibiting synaptic acetylcholine receptors (Hashimotodani et al. 2005, release of glutamate and GABA respectively (Kano Kano et al. 2009). In the hippocampus, 2-AG release et al. 2009) (Fig. 2). The presence of molecules of the is markedly enhanced by simultaneous depolarization eCB system, such as the eCBs, CB1R, as well as enzymes and input via Gq-coupled receptors, a phenomenon involved in eCB metabolism of during neuronal devel-
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