Why do cannabinoid receptors have more than one endogenous ligand?

Abstract

The endocannabinoid system was revealed following the understanding of the mechanism of action of marijuana's major psychotropic principle, Δ(9)-tetrahydrocannabinol, and includes two G-protein-coupled receptors (GPCRs; the cannabinoid CB1 and CB2 receptors), their endogenous ligands (the endocannabinoids, the best studied of which are anandamide and 2-arachidonoylglycerol (2-AG)), and the proteins that regulate the levels and activity of these receptors and ligands. However, other minor lipid metabolites different from, but chemically similar to, anandamide and 2-AG have also been suggested to act as endocannabinoids. Thus, unlike most other GPCRs, cannabinoid receptors appear to have more than one endogenous agonist, and it has been often wondered what could be the physiological meaning of this peculiarity. In 1999, it was proposed that anandamide might also activate other targets, and in particular the transient receptor potential of vanilloid type-1 (TRPV1) channels. Over the last decade, this interaction has been shown to occur both in peripheral tissues and brain, during both physiological and pathological conditions. TRPV1 channels can be activated also by another less abundant endocannabinoid, N-arachidonoyldopamine, but not by 2-AG, and have been proposed by some authors to act as ionotropic endocannabinoid receptors. This article will discuss the latest discoveries on this subject, and discuss, among others, how anandamide and 2-AG differential actions at TRPV1 and cannabinoid receptors contribute to making this signalling system a versatile tool available to organisms to fine-tune homeostasis.

Figure 1.

Different functions at different receptors for brain anandamide and 2-AG. Anandamide (structure highlighted in pink) and 2-AG (structure highlighted in light green) are depicted as being produced (thin brown arrows) from both pre- and post-synaptic intracellular membranes and from post-synaptic plasma membranes, respectively. Anandamide, by acting at pre-synaptic CB1 receptors, may participate in ‘tonic’ suppression of GABAergic signalling in organotypic hippocampal cultures [40], whereas at pre-synaptic TRPV1 it stimulates glutamate release, thereby participating in some pathological conditions (shown in italics; see text). By acting at post-synaptic TRPV1, anandamide either reduces glutamate signalling and produces long-term depression (LTD) by stimulating AMPA receptor (AMPAR) endocytosis [41,42] or, as shown in MSNs of the striatum [43], it inhibits 2-AG biosynthesis and retrograde action at CB1 receptors [44], with potential consequences on endocannabinoid-mediated retrograde control of DSE and DSI, LTD and LTP. 2-AG can also act at post-synaptic CB1 receptors, thereby mediating ‘slow self-inhibition’ of neocortical interneurons [45]. Finally, 2-AG is the likely agonist at the CB1 receptor on astrocytes, which is recently emerging as the possible mediator of a series of biological actions listed in the figure [–49], and at CB2 receptors in the same cells as well as in microglia, with strong implications for the inhibition of neuroinflammation and potential therapeutic use in several neuroinflammatory disorders [50,51]. MSN, medium spiny neurons; LTP, long-term potentiation; AMPA, 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid; DSE, depolarization-induced suppression of excitation; DSI, depolarization-induced suppression of inhibition.