Noncanonical Activity of Endocannabinoids and Their Receptors in Central and Peripheral Synapses

This review focuses on new aspects of endocannabinoid functions and mechanisms of activity in central and peripheral synapses, different from the general viewpoint that endocannabinoids are retrograde signaling molecules, which inhibit neurotransmitter release by activating specific presynaptic endocannabinoid receptors CB1 and CB2. Biased agonism of the endogenous and synthetic cannabinoids as well as ability of the CB-receptors to couple not only with classical G_i-proteins, but also with G_s- and G_q-proteins and, moreover, with β-arrestins (thereby triggering additional signaling pathways in synapses) are described here in detail. Examples of noncanonical tonic activity of endocannabinoids and their receptors and their role in synaptic function are also presented. The role of endocannabinoids in short-term and long-term potentiation of neurotransmitter release in central synapses and their facilitating effect on quantal size and other parameters of acetylcholine release in mammalian neuromuscular junctions are highlighted in this review. In conclusion, it is stated that the endocannabinoid system has a wider range of various multidirectional modulating effects (both potentiating and inhibiting) on neurotransmitter release than initially recognized. Re-evaluation of the functions of endocannabinoid system with consideration of its noncanonical features will lead to better understanding of its role in the normal and pathological functioning of the nervous system and other systems of the body, which has an enormous practical value.