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Alternative Interacting Sites and Novel Receptors for Cannabinoid Ligands

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Alternative Interacting Sites and Novel Receptors for Cannabinoid Ligands Chapter 9 Alternative Interacting Sites and Novel Receptors for Cannabinoid Ligands Attila Köfalvi Abstract The previous chapters provided us with detailed reviews on the molecu- lar biology and pharmacology of major endocannabinoid and endovanilloid ligands (namely, anandamide and 2-arachidonoylglycerol) and their receptors (CB1, CB2 and TRPV1 receptors), which altogether can be termed as “canonical knowledge”. Still, experimental findings often display mismatches with this canonical knowledge: in the last decade, a rapidly increasing number of studies have reported “non-canonical”, “unusual” pharmacological profiles for certain cannabinoid ligands and receptors. Furthermore, from time to time results are explained by suggesting the involvement of a “new receptor”. The present chapter attempts to give a helpful guideline about how to evaluate “non-canonical” results in the cannabinoid field. All the major topics of “non-canonical” cannabinoid pharmacology, namely interactions of endogenous and exogenous cannabinoid and vanilloid ligands with (1) CB1 receptor splice variants, (2) CB1 receptor heterodimers and other non-ionotropic receptors, (3) ligand- and voltage- gated ion channels and finally, (4) neurotransmitter uptake systems are thoroughly reviewed. For sake of simplicity, studies reporting unknown cannabinoid receptors without sufficient investigation of other already defined targets are not discussed here. Finally, this review highlights that the “unorthodox sites of action” may be an una- voidable consequence of evolution, providing novel ideas and pharmaceutical targets to modulate signaling systems in neuropsychiatric disorders. Introduction Phylogenetically, the endocannabinoid and the endovanilloid systems have been present for a very long period. Several invertebrates possess the same neuroactive hybrid endocannabinoid/endovanilloid (mostly arachidonic acid-derivative) lig- ands like mammalians. In addition, these substances activate both ionotropic and metabotropic receptors, being basically similar to the mammalian counterparts (Salzet and Stefano, 2002; McPartland and Glass, 2003; Anday and Mercier, 2005). It seems entirely plausible for cells and organisms to detect and respond to the changes of the external milieu with the changes in a physicochemically sensitive A. Köfalvi (ed.), Cannabinoids and the Brain. 131 © Springer 2008 132 A. Köfalvi relay system, which can be found between the external and the internal space, i.e. the plasma membrane. Since plasma membranes are rich in arachidonic acid- derivative lipids, it seems logical that deliberation of these substances upon changes in membranes’ physicochemical properties could be responsible for signaling. Then the signal has to be transduced by relay proteins (ancient metabotropic recep- tors) or translated into ion entry, which either changed the electrical charge of the membrane or interacted with intracellular cation- (Ca2+?) sensing proteins to evoke responses. For instance, ancient simple multicellular aquatic animals needed to avoid water zones of disadvantageous pH and temperature. A prototypic vanilloid receptor may have been this kind of thermo- and pH-sensor, since the TRPV1 vanil- loid receptor is the main proton- and heat-gated ion channel in vertebrates, respond- ing to arachidonic acid-derivative substances such as anandamide (Nagy et al., 2004; see Chap. 8). In line with this hypothesis, it is assumed that prototypic vanil- loid receptors preceded cannabinoid receptors in evolution (McPartland and Glass, 2003). With the appearance of more complex and bigger animal organisms in the evolution process, changes had to be detected also in the internal extracellular milieu. Given the complexity of the desired responses, several novel ion channels _ evolved, which gave relatively selective access to Na+ and/or Ca2+ or K+ or Cl / _ HCo3 ions. The phylogeny tree of ion channels indicates that one ion channel was the likely ancestor of several present-day plasma membrane ion channels together with the vanilloid receptor (Moran et al., 2004). Taking into consideration that ancient endocannabinoid/endovanilloid-sensing ion channels had to exist early in evolution and that many present time ligand- and voltage-gated ion channels inter- act with endocannabinoid/endovanilloid substances and other cannabinoid ligands (see later), it is assumed that the ancestor of a number of present-time ion channels was originally a vanilloid receptor prototype, which evolved into several new types, whose main function became different from the function of recognition of lipid substances. Nonetheless, they still preserve something from the original receptor– ligand interacting site. Although this assumption is based on certain genetic and functional evidence, recent novel approaches have revealed alternative evolution- ary trajectories for the development of homologue, ortologue and paralogue recep- tors and enzymes for the endocannabinoid/endovanilloid systems (Elphick and Egertová, 2005; McPartland et al., 2006). In the following, the non-conventional (“unorthodox”) interactions between ligands and target proteins will be summa- rized, and they all are also listed in Table 1. CB1 Receptor-Mediated Non-Canonical Effects Alternative Signaling at CB1 Receptor Homodimers Before jumping to the conclusion of the involvement of a hypothetical “CB3” receptor, one should first consider whether results are not due to variations in the pharmacological Table 1 Interaction of frequent endogenous and exogenous cannabinoid, vanilloid and related substances with rodent and human intra- and extracellular ReceptorsforCannabinoidLigands InteractingSitesandNovel 9 Alternative 133 targets AEA, ABN- 2-AG mAEA WIN-2 WIN-3 ∆9-THC HU-210 CP55940 CBD Cannabidiol Cannabinol NADA CB1R + + + ø + + + ø − + + CB1AR+ø+ + ++ CB1BR+ø+ + ++ CB2R+++−+++ø ++ TRPV1Rø+ø øø øøø+ + ABN-CBDR ø + ø ø + − GPR55 + + ø + + Imidazoline R + − + A1R M1/4R−ø PPARα PPARγ ++ 5-HT3AR−−− − − α7 nAChR − − ø ø ø GlyR − −+a −ø + Cav1−−ø ø ø− Cav2−−−−− − Cav3−øø−ø VGSCs − − Kv1.2 − − DR Kv −− (continued) Table 1 (continued) 134 AEA, ABN- 2-AG mAEA WIN-2 WIN-3 ∆9-THC HU-210 CP55940 CBD Cannabidiol Cannabinol NADA BK +b TASK-1 ø − − ø ø − TASK-3 − − HCN1 TRPV4R++ TRPA1R++ + TRPC1Røø + +ø + NMDAR + ø ENaC DAT − − − SerT − − GluT1,2 −− GlyT1A ++ Noladin PEA OEA Virodhamine ether SR141716A AM251 JWH015 AM404 Capsaicin Ccapsazepine I-RTX c CB1R+ø+ø+−+− −ø øø ø ø CB1ARøø− CB1BRøø− d CB2R− ++øø−ø+øø ø ø TRPV1R+ øøø++−− A. Köfalvi ABN-CBDR + + − ø GPR55 + + − − + Imidazoline R − 9 Alternative Interacting Sites and Novel ReceptorsforCannabinoidLigands InteractingSitesandNovel 9 Alternative 135 A1R−− M1/4Rø PPARα ++ PPARγ 5-HT3AR − α7 nAChR − GlyR Cav1 Cav2−−−−− Cav3− VGSCs − − − − − Kv1.2 DR Kv BKCa − TASK-1 TASK-3 HCN1 − TRPV4R TRPA1R ø TRPC1R−− NMDAR ENaC − DAT − (continued) Table 1 (continued) 136 Noladin PEA OEA Virodhamine ether SR141716A AM251 JWH015 AM404 Capsaicin Ccapsazepine I-RTX SerT GluT1,2 − GlyT1A For further information, see text. For efficacy and potency values at CB1 and CB2 receptors consult the previous chapter. Only those interactions are listed that develop up to 10 µM concentration of the ligand. Symbols: +, facilitation, activation, or (partial) agonism; −, inhibition, direct blockade, or antagonism; ø, reported lack of effect; + ø, reports exist on weak agonism and lack of effect as well; empty cells, data not available. Abbreviations for ligands: 2-AG, 2-ara- chidonoyl glycerol; AEA, anandamide; mAEA, R-methanandamide; WIN-2, WIN55212-2; WIN-3, WIN55212-3, the CB1 receptor receptor-inactive entan- tiomer; ∆9-THC, ∆9-tetrahydrocannabinol, the main psychoactive constituent of marijuana; ABN-CBD, abnormal-cannabidiol; NADA, N-arachidonoyl dopamine; PEA, palmitoylethanolamide; OEA, N-oleoylethanolamide; I-RTX, iodoresiniferatoxin. Abbreviations for targets: CB1R, CB1 receptor; CB1AR and CB1BR, human CB1 receptor splice variants A and B; CB2R, CB2 receptor; TRPV1R, transient release potential family “Vanilloid-type 1”; ABN-CBDR, abnor- α mal-cannabidiol receptor; GPR55, G protein-coupled orphan receptor Nr 55; A1R, adenosine A1 receptor; M1/4R, muscarinic M1 and M4 receptors; PPAR and γ α γ α α PPAR , peroxisome proliferator-activated receptors and ; 5-HT3AR, serotonin 5-HT3 receptor; 7 nAChR, 7 nicotinic acetylcholine receptor; GlyR, gly- 2+ 2+ + cine receptor; Cav1, L-type Ca channels; Cav2, N-, P/Q- and R-type channels; Cav3, T-type Ca channels; VGSCs, voltage-gated Na channels, Kv1.2, + 2+ + Shaker-type voltage-sensitive potassium channels; DR Kv, delayed rectifier voltage-sensitive K channels; BKCa, Ca -activated large-conductance K channel type BK; TASK-1 and TASK-3, two-pore-domain acid sensitive background K+ channel types 1 and 3; HCN1, hyperpolarization-activated cyclic nucleotide- gated channel type 1; TRPV4R, transient release potential family “Vanilloid-type 4” receptor; TRPA1R, transient release potential family “Ankyrin-type 1” receptor; TRPC1R, transient release potential family “Canonical-type 1” receptor; NMDAR, N-methyl-d-aspartate NR1/NR2A receptor; ENaC, Amiloride- + sensitive epithelial Na channel; DAT, dopamine transporter; Sert, serotonin transporter; GluT1,2, glutamate transporters 1 and 2; GlyT1A, glycine transporter 1A. AEA and mAEA are taken together because apparently there is no major difference in their effects on the targets listed here aDepending on the concentration of glycine and the site of the receptor (see text) bMediated by a presumable cytosolic factor cWeak endogenous
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