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Review
, 34 (6), 304-15

Supply and Demand for Endocannabinoids

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Review

Supply and Demand for Endocannabinoids

Bradley E Alger et al. Trends Neurosci.

Abstract

The endocannabinoid system consists of G-protein-coupled cannabinoid receptors that can be activated by cannabis-derived drugs and small lipids termed endocannabinoids (eCBs) plus associated biochemical machinery (precursors, synthetic and degradative enzymes, transporters). The eCB system in the brain primarily influences neuronal synaptic communication, and affects biological functions - including eating, anxiety, learning and memory, growth and development - via an array of actions throughout the nervous system. Although many aspects of synaptic regulation by eCBs are becoming clear, details of the subcellular organization and regulation of the eCB system are less well understood. This review focuses on recent investigations that illuminate fundamental issues of eCB storage, release, and functional roles.

Figures

Figure I
Figure I
Figure 1
Figure 1. Hypothetical models of three different modes of 2-AG signaling
A. In a conventional on-demand synthesis model, 2-AG synthesis is tightly linked to demand, which is triggered by neuronal activation. Stimulation causes [Ca2+]i elevation and/or G- protein (Gq/11) activation, leading to activation of the synthetic enzyme for 2-AG, DGL. Once released into the synaptic cleft, 2-AG binds to presynaptic CB1Rs and suppresses synaptic transmission. Presynaptic MGL is a major degradative enzyme for 2-AG, while another degradative enzyme, ABHD6 is located postsynaptically. B. An on-demand release model postulates de-coupling between synthesis and release of 2-AG. 2-AG can be constitutively synthesized in, but not immediately released from, unstimulated neurons. It is proposed to be stored in biochemically undefined pre-formed pools. Activation of DGL in resting neurons is sensitive to the basal level of [Ca2+]i, constitutive G protein activation, or unknown mechanisms. Stimulation-induced signals mediated by Ca2+ and/or G proteins trigger the release of 2-AG. C. In the combined model, both constitutive release from unstimulated cells and stimulation-induced 2-AG mobilization occur. In unstimulated neurons, 2-AG is synthesized as in B, but is also constitutively released into the extracellular space. Neuronal stimulation increases synthesis and induces stimulated release of additional 2-AG.
Figure 2
Figure 2. Functional distinctions among intracellular 2-AG pools
A. Measured differences in basal amounts of 2-AG in DGLα−/− and wild type mice [59][60] supports the postulation of three functionally distinct pools of 2-AG in neurons: 1) basal 2-AG produced independently of DGLα, possibly by DGLβ, although the source is unknown (“?”), 2) basal 2-AG synthesized by DGLα, and, 3) 2-AG that is produced and released upon stimulation such as an increase in [Ca2+]i or activation of Gq/11 proteins. The basal pools are present in “unstimulated” neurons and might not participate in constitutive retrograde signaling onto presynaptic terminals, whereas the stimulus-induced 2-AG mediates retrograde signaling (thus is considered a “signaling pool”). B. Ablation of DGLα (in two independent mouse models [59, 60]) does not eliminate basal 2-AG, as about 20% remains; this appears to constitute a basal, non-signaling pool. C. Stimulation of neurons with high K+ and DHPG increases the 2-AG levels to twice the total basal amount in wild-type mice (the “signaling” pool in panel A), whereas it fails to change 2-AG levels in DGLα−/− tissue, consistent with the idea that DGLα-independent 2-AG (mediated by “?” in panel A) constitutes a basal, non-signaling pool. Modified, with permission from [60] (panels C and B, left) and [65] (panel B, right).
Figure 3
Figure 3. Hypothetical mobilization of 2-AG
The hypothesis of distinct 2-AG pools may further suggest that differences in the mechanisms of 2-AG mobilization can help reconcile apparent discrepancies between observations produced by pharmacological and genetic silencing of DGL. A. In a resting neuron in wild type animals, basal 2-AG is produced by either DGLα-dependent or -independent mechanisms, and most of it remains in the cell and does not substantially activate presynaptic CB1Rs constitutively. B. In stimulated neurons, Ca2+ and/or G proteins activate DGLα-dependent synthesis of 2-AG, which is then released and mediates retrograde signaling. Simultaneously, neuronal activation may trigger 2-AG release from a basal pre-formed pool. C. DGL inhibitors are sometimes ineffective in blocking Ca2+- or G protein-dependent 2-AG signaling (see text for examples). This could be explained if Ca2+ or G proteins facilitate the release process per se of 2-AG from a pre-formed basal 2-AG pool. Acute blockade of DGLα would inhibit 2-AG synthesis, but would not immediately deplete the pre-formed pool. D. In a DGLα−/− neuron, the DGLα-dependent portion of basal 2-AG pool is eliminated (see also Fig. 2B). E. Stimulation of DGLα−/− neurons will fail to mobilize any 2-AG, because the formation of all releasable 2-AG has been abolished (also Fig. 2C).

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