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, D 9-tetrahydrocannabinol, and includes two G-proteincoupled 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.

From Phytocannabinoids to Cannabinoid Receptors and Endocannabinoids: Pleiotropic Physiological and Pathological Roles Through Complex Pharmacology

“…Indeed, TRPV1 antagonism, knockout, and/or desensitization via capsaicin pretreatment abrogate several pharmacological effects of AEA and so does neonatal capsaicin treatment (744). Recently, also the other major endocannabinoid, 2-AG, was suggested to activate TRPV1, although less potently than AEA (213).…”

The Endocannabinoid System and its Modulation by Phytocannabinoids

“…Anandamide was later found also to antagonize TRP channels of melastatin type-8 (TRPM8), which are instead activated by low temperatures and menthol [8], whereas the other cold-activated TRP, the TRP channel of ankyrin type-1 (TRPA1), activated by mustard oils, was sensitive only to high micromolar concentrations of the endocannabinoid. The stimulatory, and subsequently desensitizing, effects of anandamide at TRPV1 have been reported in hundreds of studies and represent one of the most important mechanisms, after CB1 activation, through which this lipid mediator exerts its biological functions [9]. Recently, 2-AG was also shown to activate TRPV1, although at concentrations higher than those required to anandamide to produce the same effect [10,11].…”

Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility

“…These endocannabinoids can be synthesized and inactivated independently, while they also act promiscuously (i.e., do not only act on cannabinoid receptors). This allows for a high degree of differential flexibility of their actions, thereby making the ECS a highly complex system to understand [24].…”