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The Endocannabinoid System and Invertebrate Neurodevelopment and Regeneration

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The Endocannabinoid System and Invertebrate Neurodevelopment and Regeneration International Journal of Molecular Sciences Review The Endocannabinoid System and Invertebrate Neurodevelopment and Regeneration Tristyn L. Clarke 1, Rachael L. Johnson 1 , Jonathan J. Simone 1,2,3 and Robert L. Carlone 1,2,* 1 Department of Biological Sciences, Brock University, 1812 Sir Isaac brock Way, St. Catharines, ON L2S 3A1, Canada; [email protected] (T.L.C.); [email protected] (R.L.J.); [email protected] (J.J.S.) 2 Centre for Neuroscience, Brock University, 1812 Sir Isaac brock Way, St. Catharines, ON L2S 3A1, Canada 3 eCB Consulting Inc., P.O. Box 652, 3 Cameron St. W., Cannington, ON L2S 3A1, Canada * Correspondence: [email protected] Abstract: Cannabis has long been used for its medicinal and psychoactive properties. With the rela- tively new adoption of formal medicinal cannabis regulations worldwide, the study of cannabinoids, both endogenous and exogenous, has similarly flourished in more recent decades. In particular, research investigating the role of cannabinoids in regeneration and neurodevelopment has yielded promising results in vertebrate models. However, regeneration-competent vertebrates are few, whereas a myriad of invertebrate species have been established as superb models for regeneration. As such, this review aims to provide a comprehensive summary of the endocannabinoid system, with a focus on current advances in the area of endocannabinoid system contributions to invertebrate neurodevelopment and regeneration. Keywords: AEA; 2-AG; CB1; CB2; endocannabinoid; regeneration; neurodevelopment; invertebrate Citation: Clarke, T.L.; Johnson, R.L.; Simone, J.J.; Carlone, R.L. The Endocannabinoid System and Invertebrate Neurodevelopment and 1. Historical Introduction to Cannabis and Endocannabinoids Regeneration. Int. J. Mol. Sci. 2021, 22, Global interest in the investigation of cannabis, cannabinoids, and the endocannabi- 2103. https://doi.org/10.3390/ noid system has burgeoned in recent years, with numerous countries around the world in- ijms22042103 troducing regulations allowing for the production of, and access to, cannabis and cannabis- derived products for medical purposes. While the adoption of formal medical cannabis Academic Editor: Irmgard Tegeder regulations is relatively new in a global context, the medicinal and psychoactive properties of the plant and its derivatives have been appreciated for thousands of years. Received: 21 January 2021 Therapeutic uses of Cannabis were first described in the Pen Ts’ao Ching, the world’s Accepted: 17 February 2021 oldest pharmacopoeia, for treatment of rheumatic pain, female reproductive disorders, and, Published: 20 February 2021 when taken with wine, as an anesthetic during surgical procedures [1]. In the 1930s, (–)trans- D9-tetrahydrocannabinol (D9-THC) was identified as the major psychoactive compound in Publisher’s Note: MDPI stays neutral Cannabis sativa L., the structure of which, however, was not determined until nearly 30 years with regard to jurisdictional claims in later (Figure1A) [ 2–8]. Initially, the lipophilicity of D9-THC was thought to non-specifically published maps and institutional affil- disrupt cell membranes, thus inducing its effects independent of receptor interactions [9]. iations. However, further studies established the presence of specific inhibitory G protein-coupled receptors (GPCRs), the cannabinoid receptor type-1 (CB1) and type-2 (CB2), through which D9-THC exerts its effects [2,10–12]. Subsequent explorations into the physiological roles of these receptors determined that they bind with varying affinity to a number of endoge- Copyright: © 2021 by the authors. nous lipid ligands (endocannabinoids), most notably N-arachidonoylethanolamide (AEA or Licensee MDPI, Basel, Switzerland. anandamide) and 2-arachidonyl-glycerol (2-AG) (Figure1B,C) [ 13–17]. While most research This article is an open access article into endocannabinoid signaling has focused on the contributions of AEA and 2-AG, sev- distributed under the terms and eral other compounds have been identified as endocannabinoids or endocannabinoid-like conditions of the Creative Commons Attribution (CC BY) license (https:// molecules, including 2-arachidonyl-glyceryl ether (2-AGE), virodhamine (O-AEA), N-Oleoyl creativecommons.org/licenses/by/ ethanolamine (OEA), N-palmitoyl ethanolamine (N-PEA), docosatetraenoyl-ethanolamide 4.0/). (DEA), and dihomo-γ-linolenoyl ethanolamide (DGLA) (Figure1D–I) [ 15,16,18–22]. While Int. J. Mol. Sci. 2021, 22, 2103. https://doi.org/10.3390/ijms22042103 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 24 Int. J. Mol. Sci. 2021, 22, 2103 nolamine (N-PEA), docosatetraenoyl-ethanolamide (DEA), and dihomo-γ-linolenoyl2 eth- of 24 anolamide (DGLA) (Figure 1D–I) [15,16,18–22]. While our understanding of endocanna- binoid signaling is incomplete, the diversity in known signaling compounds and modu- latorsour understanding underscores the of complexity endocannabinoid of the endocannabinoid signaling is incomplete, system and the diversitysupports inits knownrole in asignaling wide range compounds of physiological and modulators processes. underscores the complexity of the endocannabinoid system and supports its role in a wide range of physiological processes. Figure 1. Chemical structures of various cannabinoid ligands. (A) Phytocannabinoid, THC. (B,C) Endocannabinoids, AEA Figure 1. Chemical structures of various cannabinoid ligands. (A) Phytocannabinoid, THC. (B,C) Endocannabinoids, AEA and 2-AG. (D–I) Synthetic cannabinoids, 2-AGE, O-AEA, OEA, N-PEA, DEA, and DGLA. and 2-AG. (D–I) Synthetic cannabinoids, 2-AGE, O-AEA, OEA, N-PEA, DEA, and DGLA. 2. The Endocannabinoid System in Vertebrates 2.2.1. The Endocannabinoid Endocannabinoid Metabolism System in Vertebrates 2.1. EndocannabinoidEndocannabinoids Metabolism exert their neuromodulatory effects through retrograde inhibi- tionEndocannabinoids of synaptic release exert via interactions their neuromodulatory with CB1 and effects CB2 through receptors. retrograde Unlike traditional inhibition ofneurotransmitters synaptic release andvia interactions neuromodulators, with CB1 endocannabinoids and CB2 receptors. are Unlike poorly traditional water soluble neuro- and tthusransmitters are generally and neuromodulators, synthesized coupled endocannabinoids to the membrane are poorly [23]. Synthesis water soluble of AEA and occurs thus arein thegenerally post-synaptic synthesized neuron, coupled primarily to the through membrane the hydrolysis [23]. Synthesis of the of membrane AEA occurs phospho- in the postlipid-synaptic precursor neuron,N-arachidonoyl primarily phosphatidylethanolaminethrough the hydrolysis of the (NAPE) membrane by N -arachidonoylphospholipid pphosphatidylethanolamine-specificrecursor N-arachidonoyl phosphatidylethanolamine phospholipase D (NAPE) (NAPE-PLD); by N-arachidonoyl NAPE is generated phos- phatidylethanolaminefrom the membrane phospholipids-specific phospholipase phosphatidylethanolamine D (NAPE-PLD); (PE)NAPE and is arachidonicgenerated from acid thevia membrane an unspecified phospholipidsN-acyltransferase phosphatidylethanolamine (NAT) [24,25]. Hydrolysis (PE) and of NAPE arachidonic by NAPE-PLD acid via anleads unspecified to the production N-acyltransferase of a wide (NAT) variety [24,25]. of HydrolysisN-acylethanolamines of NAPE by (NAEs), NAPE-PLD including leads toAEA the (Figureproduction2A), andof a wide is regulated variety byof aN variety-acylethanolamines of upstream (NAEs), factors, includingincluding activationAEA (Fig- ureof ionotropic 2A), and is glutamate regulatedN by-methyl-D-aspartate a variety of upstream (NMDA) factors, receptors, including and activation post-synaptic of iono- re- tropicsponses glutam to calcium,ate N-methyl dopamine,-D-aspartate glutamine, (NMDA) and acetylcholine receptors, [and24,26 post–29-].synaptic While NAPE-PLD responses tois calcium, considered dopamine, the dominant glutamine, synthesis and pathwayacetylcholine for AEA, [24,26 enzymatic–29]. While conversion NAPE-PLD of is NAPE con- -/- sideredto AEA the has dominant been observed synthesis in pathway NAPE-PLD for AEAmice,, enzymatic suggesting conversion that alternative of NAPE to biosyn- AEA hasthetic been pathways observed likely in NAPE exist [30-PLD,31].-/- Indeed,mice, suggesting two additional that pathwaysalternative of biosynthetic AEA biosynthesis path- wayswere likely subsequently exist [30,31]. discovered Indeed, [ 24two,30 additional–32]. In one pathways pathway, of an AEA alternative biosynthesis phospholipase, were sub- sequentlyNAPE-PLC, discovered converts [24,30 NAPE–32 to]. phospho-anandamide In one pathway, an alternative (pAEA), which phospholipase, is then quickly NAPE de-- PLC,phosphorylated converts byNAPE the protein to phospho tyrosine-anandamide phosphatase non-receptor-type(pAEA), which 22is (PTPN22) then quickly to free dephosphorylatedanandamide [24]. Theby the second protein pathway tyrosine catalyzes phosphatase either non NAPE-receptor or lyso-NAPE-type 22 (PTPN22) via the αβ to- hydrolase domain-containing protein 4 (Abhd4) to generate the precursor, glycerophospho- arachidonoyl ethanolamide (GpAEA) [32,33]. GpAEA is then converted to AEA via the ac- tions of the metal-dependent phosphodiesterase glycerophosphodiesterphosphodiesterase Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 3 of 24 free anandamide [24]. The second pathway catalyzes either NAPE or lyso-NAPE via the αβ-hydrolase domain-containing protein 4 (Abhd4) to generate the precursor, glycer- ophospho-arachidonoyl ethanolamide (GpAEA)
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