Brain endocannabinoid signaling exhibits remarkable complexity

Highlights

• Endocannabinoid signaling is one of the most extensive systems of the mammalian brain.

• Numerous described factors inflect eCB signaling.

• Receptors oligomerisation substantially changes signalization they trigger.

• The eCB system can be used as therapeutic target.

Abstract

The endocannabinoid (eCB) signaling system is one of the most extensive of the mammalian brain. Despite the involvement of only few specific ligands and receptors, the system encompasses a vast diversity of triggered mechanisms and driven effects. It mediates a wide range of phenomena, including the regulation of transmitter release, neural excitability, synaptic plasticity, impulse spread, long-term neuronal potentiation, neurogenesis, cell death, lineage segregation, cell migration, inflammation, oxidative stress, nociception and the sleep cycle. It is also known to be involved in the processes of learning and memory formation. This extensive scope of action is attained by combining numerous variables. In a properly functioning brain, the correlations of these variables are kept in a strictly controlled balance; however, this balance is disrupted in many pathological conditions. However, while this balance is known to be disrupted by drugs in the case of addicts, the stimuli and mechanisms influencing the neurodegenerating brain remain elusive. This review examines the multiple factors and phenomena affecting the eCB signaling system in the brain. It evaluates techniques of controlling the eCB system to identify the obstacles in their applications and highlights the crucial interdependent variables that may influence biomedical research outcomes.

Introduction

The human endocannabinoid system comprises two principal ligands and two key receptors. The major endogenous ligands for CB receptors are two fatty acid derivatives: the eicosanoids N-arachidonoyl-ethanolamide (anandamide) and 2-arachidonoyl glycerol (2-AG). Two endocannabinoid receptors are known: CB1R, which is widely expressed in the brain, with lower levels observed in the peripheral circulation, and CB2R, which is mostly expressed in the peripheral circulation, predominantly in immune-related organs and cells. Both receptors contain seven transmembrane domains and are members of the class A G-protein coupled receptor (GPCR) superfamily.

CB1R has a phylogenetically conserved function, sharing 97–99% amino acid sequence identity with various mammalian species. Other species also demonstrate similar patterns of CB1R distribution in the brain (Matsuda et al., 1990a). Compared to the density of GABA, glutamate or striatal dopamine receptors, CB1 receptors appear to be as abundant in the brain as pivotal neurotransmitter receptors (Herkenham et al., 1990). In the brain, CB1Rs are widespread in the hippocampus, cerebellum, cerebral cortex, basal ganglia, amyglada and sensory motor sectors of the striatum; however, they are sparsely distributed in the brainstem, diencephalon and spinal cord (Herkenham et al., 1991; Glass et al., 1997; Van Waes et al., 2012; Chevaleyre et al., 2006). The activity, quantities and distribution pattern of the CB1 receptors seem to be specific to cell type, synapse type and even microdomain. CB1Rs are mostly distributed presynaptically, with much higher density in GABA-ergic than in glutamatergic neurons (Katona et al., 2006a; Kawamura et al., 2006; Stempel et al., 2016), and are most abundant in the hippocampal GABA-ergic interneurons, on presynaptic axon terminals (Katona et al., 1999). Even though the highest CB1R content is found on the GABA-ergic synapses of hippocampus CCK-positive interneurons, their density varies between distinct types of interneuron, resulting in differential efficacy of synaptic activity control (Katona et al., 2000; Lee et al., 2010a).

In addition, the enzymes involved in endocannabinoid metabolism, such as the AEA-degrading enzyme FAAH (fatty acid amide hydrolase), several AEA synthesizing enzymes, the 2-AG synthesizing enzymes DGL-α and DGL-β (diacylglycerol lipase α/β) and the 2-AG degrading enzyme MAGL (monoacylglycerol lipase), also demonstrate considerable subcellular segregation and varied distribution patterns in the brain (Nyilas et al., 2009; Ludanyi et al., 2011; Gao et al., 2010; Uchigashima et al., 2007; Yoshida et al., 2006; Matyas et al., 2008; Yoshida et al., 2011; Katona et al., 2006a; Gulyas et al., 2004; Uchigashima et al., 2011; Tanimura et al., 2010). In consequence, the localization, quantity and thus the activity of 2-AG, AEA and CBRs are highly controlled and site specific, resulting in a highly-complex arrangement of endocannabinoid signaling outputs. For example, the psychotropic effects of Δ⁹-tetrahydrocannabinol (Δ⁹-THC), a major terpenophenolic compound of marijuana, are mediated by CB1Rs, and its prolonged use leads to CB1R-dependent long-term memory deficits (Ledent et al., 1999; Puighermanal et al., 2009). In addition, CB1R may well play a protective role against age-dependent cognitive decline as the absence of a CB1R receptor induced degeneration of pyramidal neurons and enhanced neuroinflammation in CNR1 knock out mice: this being the gene encoding CB1R (Albayram et al., 2011).

Cannabinoid signaling involves non-cannabinoid factors that increase CB system complexity. eCBs can non-specifically activate many other receptors. For example, AEA, but not 2-AG, activates type-1 transient receptor potential vanilloid (TRPV1) ion channels that naturally serve to respond to low pH and noxious heat (Tominaga et al., 1998; Di Marzo and De Petrocellis, 2010). However, while only high concentrations of AEA preferentially activate TRPV1, low AEA concentrations activate CB1R (Moreira et al., 2012). Some other non-cannabinoid receptors that are vulnerable to eCB activation include peroxisome proliferator-activated receptors (PPARs), non-selective cation channels such as TRPA1 or TRPM8, ligand-gated ion channels including 5-HT3, metabotropic receptors including GPR55, glycine and nicotinic acetylcholine receptors, voltage-gated ion channels including T-type calcium channels and the TASK potassium channels (Witkamp, 2016; Pertwee et al., 2010). Also some non-cannabinoid ligands can activate CB receptors and these include FAAs, glycerol esters, prostamides or PG esters (Witkamp, 2016).

The present review discusses the known factors forming parts of the vast network of structural and functional dependence in the cannabinoid system of the brain. It involves the activation or inhibition of diverse signaling pathways by cannabinoid and non-cannabinoid ligands and receptors. It highlights the significance of conformational changes within receptors which allow incoming signals to be distinguished, thus inducing various interactions with distinct G-proteins and other endogenous non-G proteins. It outlines known phenomena which influence downstream signaling such as receptor oligomerisation. When emphasizing the immense complexity of the cannabinoid system in the brain, it is important to note two key points: numerous variables and their combinations are specific for a cell type and its condition, and that no two cells are the same, according to the cogent concept of somatic mosaicism (Katona and Freund, 2012; McConnelll et al., 2017; Lodato et al., 2015; Hazen et al., 2016).