Lipoxin A 4 is an allosteric endocannabinoid that strengthens anandamide-induced CB 1 receptor activation

A major advance in the field of cannabinoid research was the discovery of the endocannabinoid system, which is currently thought to consist of two G protein-coupled receptors (cannabinoid CB1 and CB2 receptors) and endogenous compounds such as arachidonoylethanolamide (i.e., anandamide; AEA; Fig. 1) and 2-arachidonoyl glycerol (2-AG) that can activate these receptors and are known as endocannabinoids (1). This system of receptors and endogenous agonists, which is also made up of enzymes that catalyze endocannabinoid biosynthesis or metabolic degradation, and of processes responsible for the cellular uptake of endocannabinoids, is thought to have numerous roles in both health and disease (2, 3). Some of these are “autoprotective” in nature and hence beneficial, with examples including the amelioration of inflammatory pain, multiple sclerosis, and Parkinson disease; whereas a few of its other roles, for example, in obesity, are “autoimpairing,” and therefore unwanted. AEA, 2-AG, and other “direct” cannabinoid receptor agonists are thought to trigger G protein-mediated signaling of CB1 and CB2 receptors by targeting orthosteric sites on these receptors (1). There is evidence, however, that the CB1 receptor also contains one or more “allosteric” sites that can be targeted by allosteric modulators in a manner that can enhance or reduce the efficacy with which direct agonists activate this receptor orthosterically (4⇓⇓–7). Just as the discovery of the CB1 receptor prompted a search for endogenous ligands for this receptor (8), so too the discovery that CB1 receptors contain allosteric sites has prompted a need to look for an endogenous CB1 allosteric modulator. This need has now been met by Pamplona et al. (9), who, in PNAS, present evidence that the endogenous anti-inflammatory ligand lipoxin A4 (LXA4; Fig. 1) can allosterically enhance AEA-induced activation of CB1 …