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

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Abstract

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 Gi-proteins, but also with Gs- and Gq-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.

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Abbreviations

2-AG:

2-arachidonoylglycerol

AC:

adenylate cyclase

ACh:

acetylcholine

AEA:

N-arachidonoylethanolamine (anandamide)

CB:

cannabinoid receptors

DAG:

diacylglycerol

DAGLα:

diacylglycerol lipase α

DSE:

depolarization-induced suppression of excitation

DSI:

depolarization-induced suppression of inhibition

GABA:

gamma-aminobutyric acid

LTD:

long-term depression

LTP:

long-term potentiation

MAPK:

mitogen-activated protein kinase

PKA:

proteinkinase A

PLC:

phospholipase C

THC:

tetrahydrocannabinol

WIN:

(R)-(+)-[2,3-Dihydro-5-methyl-3[(4-morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate salt

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This work was financially supported by the Russian Foundation for Basic Research (project no. 19-04-00616a).

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  1. Faculty of Biology, Lomonosov Moscow State University, 119234, Moscow, Russia

    Olga P. Balezina, Ekaterina O. Tarasova & Alexander E. Gaydukov

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Balezina, O.P., Tarasova, E.O. & Gaydukov, A.E. Noncanonical Activity of Endocannabinoids and Their Receptors in Central and Peripheral Synapses. Biochemistry Moscow 86, 818–832 (2021). https://doi.org/10.1134/S0006297921070038

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