Tài liệu Báo cáo khoa học: Endovanilloids Putative endogenous ligands of transient receptor potential vanilloid 1 channels docx

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Tài liệu Báo cáo khoa học: Endovanilloids Putative endogenous ligands of transient receptor potential vanilloid 1 channels docx

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MINIREVIEW Endovanilloids Putative endogenous ligands of transient receptor potential vanilloid 1 channels Mario van der Stelt and Vincenzo Di Marzo Endocannabinoid Research Group, Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, Italy Endovanilloids are defined as endogenous ligands of the transient receptor potential vanilloid type 1 (TRPV1) protein, a nonselective cation channel that belongs to the large family of TRP ion channels, and is activated by the pungent ingredient of hot chilli peppers, capsaicin. TRPV1 is expressed in some nociceptor efferent neurons, where it acts as a molecular sensor of noxious heat and low pH. However, the presence of these channels in var- ious regions of the central nervous system, where they are not likely to be targeted by these noxious stimuli, suggests the existence of endovanilloids. Three different classes of endogenous lipids have been found recently that can activate TRPV1, i.e. unsaturated N-acyldopamines, lip- oxygenase products of arachidonic acid and the endo- cannabinoid anandamide with some of its congeners. To classify a molecule as an endovanilloid, the compound should be formed or released in an activity-dependent manner in sufficient amounts to evoke a TRPV1-mediated response by direct activation of the channel. To control TRPV1 signaling, endovanilloids should be inactivated within a short time-span. In this review, we will discuss, for each of the proposed endogenous ligands of TRPV1, their ability to act as endovanilloids in light of the criteria mentioned above. Keywords: anandamide; arachidonic acid; cannabinoid; lipid; signaling; TRP; VR1. Introduction The transient receptor potential vanilloid type 1 (TRPV1) protein is a nonselective cation channel that belongs to the large family of TRP ion channels and is highly expressed in small diameter primary afferent fibers [1]. It is a molecular integrator of noxious stimuli, such as heat and low pH, and can also be activated by the pungent ingredient of hot chilli peppers, capsaicin, as well as by other plant toxins, the most potent of which is resiniferatoxin (RTX) [2]. In primary sensory neurons, TRPV1 is essential for the development of inflammatory hyperalgesia [3,4]. Although initially controversial, it has now been firmly established that TRPV1 is synthesized in cells outside the peripheral nervous system, such as keratinocytes, epithial and endo- thelial cells, where it serves as yet undefined purposes [5]. Furthermore, TRPV1 has also been found in various brain areas, including dopaminergic neurons of the substantia nigra, hippocampal pyramidal neurons, hypothalamic neu- rons, the locus coeruleus in the brainstem and in various layers of the cortex, where it might be involved in modulation of synaptic plasticity [6,7]. In the central nervous system or under normal physio- logical conditions, TRPV1 is unlikely to be activated by heat or low pH, therefore it has been suggested that other endogenous ligands of this ion channel exist. Indeed, three different classes of lipids, all derived from the metabolism of arachidonic acid (AA), have been recently characterized that can activate TRPV1, i.e. in chronological order, the endocannabinoid anandamide, some lipoxygenase products of AA, and N-arachidonoyldopamine (Fig. 1). To qualify as an ÔendovanilloidÕ, i.e. an endogenous activator of TRPV1, the compound should be formed by cells and be released in an activity-dependent manner in sufficient amounts to evoke a TRPV1-mediated response by direct binding and subse- quent activation of the channel. Finally, endovanilloid signalling should be terminated within a short time-span to allow a strict regulation of its actions. Therefore, biosyn- thetic and metabolic pathways for a putative endovanilloid should be present in close proximity to TRPV1. As the putative binding site for an endogenous ligand at TRPV1 is intracellular [8,9], it might be expected that putative endogenous ligands are produced inside the cell or, in the case of production at a more distant site, brought into the cell. In this review we will discuss the capabilities of Correspondence to V. Di Marzo, Instituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, Bldg. 70 80078 Pozzuoli (NA), Italy. Fax: + 39 081 8041770, Tel.: + 39 081 8675093, E-mail: vdimarzo@icmib.na.cnr.it Abbreviations: 12-HETE, 12-hydroxyeicosatetraenoic acid; 12S-and 15S-HPETE, 12-(S)- and 15-(S)-hydroperoxyeicosatetraenoic acid; AA, arachidonic acid; DRG, dorsal root ganglia; RTX, resinifera- toxin; TRPV1, transient receptor potential vanilloid type 1 protein. Note added during revision: During the revision process of this article, NADA was reported to exert a potent vasodilation of rat mesenteric arteries via mechanisms including TRPV1 receptors as well as cann- abinoid CB1 receptors and an as-yet-uncharacterized cannabinoid endothelial receptor [O’Sullivan, S.E., Kendall, D.A. & Randall, M.D. (2004). Br. J. Pharmacol., 141, 803–812]. (Received 16 January 2004, revised 13 February 2004, accepted 18 February 2004) Eur. J. Biochem. 271, 1827–1834 (2004) Ó FEBS 2004 doi:10.1111/j.1432-1033.2004.04081.x N-arachidonoyldopamine, lipoxygenase products of AA and anandamide to act as endogenous activators for TRPV1 in vivo in light of the above mentioned criteria. N -arachidonoyldopamine Biosynthesis N-arachidonoyldopamine was characterized originally in the striatum of bovine brain and its distribution in the rat nervous system is as follows (greatest abundance to lowest): striatum > hippocampus > cerebellum > thalamus >> dorsal root ganglia (DRG) [10]. The basal levels of N-arachidonoyldopamine are low (6 pmolÆg )1 striatum) and its stimulus-evoked formation has yet to be demon- strated [10]. Noteworthy, other congeners of this compound have been detected recently in the bovine brain, i.e. N-oleoyldopamine, N-palmitoyldopamine and N-stearoyl- dopamine [11]. Of these, N-oleoyldopamine also possesses the ability to activate TRPV1 with the same potency as N-arachidonoyldopamine [11]. N-arachidonoyldopamine can theoretically be formed through two biosynthetic pathways [10]. Firstly, a direct condensation of AA (or its Coenzyme A derivative) with dopamine has been proposed, but the enzyme responsible for this condensation has not yet been characterized. The second route is an indirect pathway in which N-arachidonoyltyrosine is converted into N-arachidonoyldopamine. Interestingly, TRPV1 mRNA was colocalized with mRNA of tyrosine hydroxy- lase in dopaminergic neurons of the substantia nigra, which project to the striatum [6]. To date, conclusive experimental evidence for either pathway is still lacking. If N-arachidonoyldopamine acts in a paracrine manner, it has to be transported into the cell to reach its site of action. In support to this hypothesis, N-arachidonoyl- dopamine was rapidly taken-up by C6 glioma cells via the rapid facilitated diffusion process [10] that is also respon- sible for anandamide transport across membranes (reviewed in [12]). Degradation The same membrane transport process carrying N-arachi- donoyldopamine into the cell can theoretically also be used to extrude it from the cell, thereby terminating its actions at TRPV1. Other possible inactivation pathways are the hydrolysis of its amide bond by a hydrolase or its methylation of the hydroxyl group of its cathechol moiety by a cathechol-O-methyl-transferase (Fig. 2). The latter route might represent the inactivation pathway in in vivo nervous tissues where this enzyme is abundant because N-arachidonoyldopamine was only very slowly hydrolysed by brain homogenates and its methylated derivative was less potent or inactive at TRPV1 [10]. Fig. 1. Chemical structures of endogenous TRPV1 ligands. Fig. 2. Metabolic pathways of N-arachido- noyldopamine. 1828 M. van der Stelt and V. Di Marzo (Eur. J. Biochem. 271) Ó FEBS 2004 Pharmacology and physiological actions N-arachidonoyldopamine is a full agonist of TRPV1 and the most potent endogenous lipid ligand discovered to date. It has a K d of approximately 5–10 l M in binding assays performed in heterologous or native expression systems, respectively [13,14]. It is five to 10-fold more potent than anandamide and almost equipotent as capsaicin in some functional assays, with an EC 50 in Ca 2+ -influx assays of approximately 50 n M at human and rat TRPV1 over- expressed in HEK293 cells. N-arachidonoyldopamine is also able to rapidly desensitize the TRPV1 receptor to subsequent capsaicin activation [10]. Its potency seems to be dependent on the cell and assay conditions used to assess its functional activity, because in rat DRG neurons (using Ca 2+ imaging) and rat TRPV1-CHO cells (using a Ca 2+ - uptake assay) its potency is in the low micromolar range (0.8–5 l M ) [10,13]. Exogenous N-arachidonoyldopamine induces, in a TRPV1-dependent manner, calcitonin gene- related peptide and substance P release from spinal cord slices and enhances hippocampal paired-pulse depression (EC 50 0.1–0.2 l M [10]). It is also able to induce TRPV1- mediated thermal hyperalgesia [10], and constriction of isolated bronchi and urinary bladder [15], albeit, in these two assays N-arachidonoyldopamine is much less potent and efficacious than capsaicin. Species differences and pharmacodynamic factors (such as reduced bioavailability and limited access to the intracellular site on TRPV1) were suggested to be responsible for these varying potencies [15]. As yet, no TRPV1-mediated physiological or pathological conditions have been attributed to endogenously formed N-arachidonoyldopamine. Lipoxygenase products of arachidonic acid Biosynthesis Various oxygenated AA derivatives were shown to activate TRPV1 [16]. 12-(S)- and 15-(S)-hydroperoxyeicosatetrae- noic acid (12S-and15S-HPETE) possessed the highest potency. These AA metabolites can be produced by lipoxygenases that introduce molecular oxygen in a regio- and stereoselective dependent manner in AA released from the membrane by phospholipase A 2 enzymes (Fig. 3) [17]. Several isoforms for both 12S-and15S-lipoxygenases have been identified. 15(S)-Lipoxygenase-1 has been found in human eosinophils and a second isoform, 15(S)-lipoxyge- nase-2, is expressed in the prostate, lung, cornea and hair roots [18]. There are three 12-lipoxygenase isoforms that have a broad tissue distribution, including the lung, pineal gland, spleen, macrophages and keratinocytes [19]. 12S- Lipoxygenase has also been found in the canine brain, including basal ganglia, hippocampus and hypothalamus [20,21]. Importantly, 12-lipoxygenase mRNA was found to be coexpressed with TRPV1 in rat DRG neurons [22]. However, colocalization with TRPV1 in neurons of the central nervous system has not been studied yet. Lipoxygenases are not stimulated by calcium, but their substrate AA can be liberated from the membrane by an agonist-stimulated increase in intracellular calcium that activates Ca 2+ -dependent phospholipases A 2 [17]. For example, it was shown that the potent inflammatory mediator bradykinin could induce the production of 12-hydroxyeicosatetraenoic acid (12-HETE), a metabolic product of 12-HPETE, from rat primary sensory neurons [22]. Furthermore, AA can be produced from anandamide by hydrolysis of its amide bond by fatty acid amide hydrolase [23]. Interestingly, 12/15-lipoxygenases can also accept AA esterified into membrane lipids and the endo- cannabinoid anandamide as a substrate [18,24,25–27]. The lipoxygenase products of anandamide are potent endo- genous inhibitors of fatty acid amide hydrolase [27,28] and might stimulate TRPV1 themselves [29,30], although attempts to demonstrate their direct activity at these receptors have given negative results [8,31]. Degradation The hydroperoxy group in the lipoxygenase products of AA is very labile and easily reduced into a hydroxy-group by glutathione peroxidases, which might constitute an inacti- vation pathway, because the reduced lipoxygenase products are far less potent on TRPV1 (Fig. 3) [16]. Pharmacology and physiological actions 12-HPETE could displace [ 3 H]RTX from recombinant TRPV1-HEK293 cells more potently than capsaicin (K i ¼ 0.35 and 2.5 l M , respectively) [22]. However, in inside-out patches of neonatal rat dorsal root ganglia neurons 12(S)- and 15(S)HPETE had an EC 50 values of approximately 8 l M , which was seven- to eightfold higher than that for capsaicin as measured by single channel current recordings [16]. To date, no pharmacological study has described the activity of exogenous lipoxygenase products on typical TRPV1-mediated responses in vivo or Fig. 3. Biosynthetic and metabolic pathways of 12- and 15-HPETE. Pathways indicated (a) under physiological conditions and during pharmacological assays and (b) during pharmacological assays. Ó FEBS 2004 Endovanilloids (Eur. J. Biochem. 271) 1829 ex vivo, such as hyperalgesia, and vasodilation or broncho- or urinary bladder constriction. This lack of data might be due to practical problems such as the instability of these compounds. However, some studies indirectly suggest that endogenously produced lipoxygenase metabolites are responsible for TRPV1-mediated actions in vivo.For example, protease-activated receptor-2 activation causes endothelium-dependent coronary vasodilation in a capsaze- pine-sensitive manner, which might be mediated through a lipoxygenase metabolite, because three structurally different lipoxygenase inhibitors were able to attenuate this response [32]. In their elegant study, Shin et al. provided evidence that 12(S)-HPETE is produced endogenously in sensory neurons upon stimulation of sensory nerve endings by the inflammatory mediator bradykinin, and activates TRPV1. This might suggest that this lipoxygenase product is important in the development of inflammatory pain [22]. As TPRV1 activation in bronchial afferents leads to bronchoconstriction and lipoxygenase activity is up-regula- ted during inflammatory reactions, it has also been hypo- thesized that lipoxygenase product-mediated activation of TRPV1 might contribute to bradykinin-induced hypersen- sitivity of airways and asthma [33]. Subsequent studies performed with TRPV1 null mice have shown, however, that whereas TRPV1 may have a modulatory role in the activation of bronchopulmonary C-fibres induced by brady- kinin, it is not required for action potential discharge evoked by this stimulus [34]. Anandamide Biosynthesis The endogenous lipid anandamide was isolated from pig brain in 1992 [35] and characterized originally as an endogenous agonist of cannabinoid receptors. Therefore, its biosynthetic and metabolic pathways have been studied in great detail (Fig. 4) [36,37]. In 1999, it was reported that anandamide could also activate rat TRPV1 receptors in mesenteric arteries as well as both rat and human TRPV1 in heterologous expression systems. This made this compound the first discovered endogenous ligand for TRPV1 [38,39]. It is widely recognized that anandamide is not stored in vescicles like other mediators but by analogy with other eicosanoids, is produced Ôon demandÕ in a Ca 2+ -dependent manner [40]. This is the result of a biosynthetic mechanism relying on the existence of a phospholipid precursor for anandamide, and of a Ca 2+ -sensitive phosphodiesterease for the conversion of this precursor into anandamide. Although the biosynthetic route underlying the formation of anandamide has been extensively studied, the phospho- lipase D (PLD) responsible for release of anandamide from its precursor N-arachidonoylphosphatidylethanolamine has only been purified recently, cloned and characterized [41]. It is still unknown which type of neurons express the biosynthetic enzymes, and therefore a classification of ÔanandamidergicÕ neurons is not yet possible. Nevertheless, anandamide has been found in all the brain regions which express TRPV1, with high levels in hippocampus, substantia nigra and striatum. Sensory neurons of rat dorsal root ganglia are also able to produce anandamide in high amounts [42]. Degradation Theoretically, intracellular anandamide can be inactivated through two concurrent processes [43]. Firstly, anandamide might be extruded from the cell via a selective transporter. This might be the same protein that is responsible for the uptake of anandamide from the extracellular space into the cell, because, among other things, anandamide has been proposed to be transported by a carrier-facilitated diffusion process according to its concentration gradient across the membrane [44,45]. This process might be bi-directional, because it is neither dependent on external Na + nor affected by metabolic inhibitors. Anandamide uptake (and possibly its release) can be stimulated by NO [28] and blocked by selective inhibitors [46–48]. However, the elusive nature of the putative protein responsible for endocannabinoid transport across membranes has initiated a debate on its existence [12]. Secondly, once inside the cell, anandamide undergoes metabolism via two possible pathways: hydrolysis and oxygenation [43,49,50]. The amide bond in anandamide can be hydrolysed, which yields AA and ethanolamine. Although AA does not activate TRPV1 by itself, it is a substrate for lipoxygenases, which can produce metabolites active on this channel (see above). Therefore, when studying the effects of exogenous anandamide at TRPV1 its hydro- lysis should be taken into account. Fatty acid amide hydrolase, the protein responsible for anandamide hydro- lysis in vivo, has been cloned and studied in detail [23,51]. It is an intracellular membrane-associated hydrolase with high activity in several brain areas, including the hippocampus, Fig. 4. Biosynthetic and metabolic pathways of anandamide. 1830 M. van der Stelt and V. Di Marzo (Eur. J. Biochem. 271) Ó FEBS 2004 subtantia nigra and striatum [52]. At the moment it is not known whether TRPV1 is coexpressed with fatty acid amide hydrolase in the same neurons. Much less is known about the oxygenation pathways. Lipoxygenase- and cycloxygenase-catalyzed oxygenation of anandamide has been shown to generate a vast array of possibly biologically active compounds, such as hydro- peroxy-anandamides and prostamides [50]. While the latter compounds are not able to activate TRPV1, and hence conversion of anandamide by cyclooxygenase-2 represents an inactivation pathway, the lipoxygenase products of anandamide might still be able to activate this channel [29,30], much in the same way they appear to be still active to some extent also on cannabinoid receptors [27]. Pharmacology and physiological actions The pharmacology of anandamide actions on TRPV1 has recently been reviewed extensively by Ross [53]. In short, anandamide displaces [ 3 H]RTX from TPRV1 with a K i of  2 l M in recombinant cell lines, which is similar to that of capsaicin [54,55]. However, its potency in various assays is usually five- to 10-fold lower than that of capsaicin. For example, in high recombinant expression systems, the EC 50 value for anandamide-induced Ca 2+ -influx ranges from 0.4 to 5 l M and anandamide appears to act as a full agonist, while in native systems, such as Ca 2+ -influx and inward current in DRG neurons, anandamide is a partial agonist with a potency varying from 6 to 10 l M [10,16,56]. In isolated organs, exogenous anandamide has also been shown to induce typical TRPV1-mediated effects with varying potency and efficacy. For example, anandamide induces CGRP-mediated relaxation of blood vessels with an EC 50 of 0.3–0.8 l M as a full agonist [38,57,58], while it is much less potent when causing tachykinin-mediated con- striction of bronchi and urinary bladder (EC 50 varying from 6to>10l M )[57]. Due to its low potency and partial agonism in some assays, anandamide’s ability to be a physiologically relevant activator of TRPV1 was originally controversial [59]. However, it is now well established that the potency and efficacy of (exogenous) anandamide at TRPV1 receptors are influenced by a multitude of different factors, ranging from assay conditions and species differences to TRPV1 modi- fication and the ability of anandamide to reach the intracellular binding site on TRPV1. Thus, due to its low intrinsic efficacy, anandamide is a partial agonist in tissues with a low receptor reserve (e.g. bronchi), but it appears to be a full agonist in tissues with a high receptor reserve such as the mesentery artery [53,57]. In several pathological conditions, TRPV1 activity/expression is upregulated, and this results in a significantly higher efficacy of anandamide [60]. It has been shown that ethanol, which is frequently used as a vehicle to dissolve anand- amide, can potentiate TRPV1 mediated-responses to anandamide via an unknown mechanism [61], whereas bovine serum albumin and plastic may prevent anandamide from reaching the intracellular binding site [55]. Apart from high temperature (> 43 °C) and low pH (< 7.2), which may activate and/or sensitize TRPV1, multiple signalling pathways have also been shown to interact with TRPV1 to modify its gating properties and response to anandamide [1]. The channel might be sensitized by (a) removal of its inhibition by phosphatidylinositolbisphosphate, via PLC- mediated hydrolysis [62], (b) protein kinase C-catalysed phosphorylation following PLC-mediated diacylglycerol release [63,64], (c) protein kinase A-mediated phosphoryla- tion [31], (d) phosphorylation induced by by calmodulin- dependent protein kinase II [65] or (e) voltage-dependent priming [66]. Conversely, TRPV1 can be rapidly desensi- tized subsequent to activating stimuli by a calmodulin- dependent step [67]. As discussed in the previous paragraph, the level of expression and the activity of the putative anandamide transporter, which may vary in different types of cells, is of crucial importance for exogenous anandamide to reach its cytosolic binding site at TRPV1 [8,57]. The rapid metabo- lism of anandamide inside cells may also limit its activation of TRPV1 [8,54,68], or potentiate its effect in the case of lipoxygenase-mediated conversion [29,30]. N-acyl-ethanolamine anandamide congeners, which are cobiosynthesized with anandamide from the phospholipase D-dependent hydrolysis of the corresponding N-acyl- phosphatidylethanolamines [41], also significantly enhance ananadamide effects at TRPV1 [55,69]. One of these compounds, N-oleoylethanolamine, was even found to be able to activate TRPV1 per se under certain conditions [70]. Last, but not least, anandamide functional activity at TRPV1 can be significantly masked by its concomitant activity on cannabinoid CB 1 receptors, particularly in those tissues and cells where the two receptors are coexpressed and are coupled to opposing biological effects [80]. In this case, a significant enhancement of the potency of anand- amide at TRPV1 can be observed in the presence of CB 1 antagonists [80]. At the moment, very few studies have been reported in which endogenous anandamide was shown to activate TRPV1 in vivo. Although exogenous anandamide induces TRPV1-mediated vasodilation, calcium influx in DRG neurons and bronchoconstriction in situ, which might suggest that endogenous anandamide is involved through TRPV1 in physiological processes such as blood pressure, pain sensation and airway responsiveness, respectively, to date there is only little experimental data providing conclu- sive evidence supporting these hypotheses [14,60,71,72]. However, recently the first example of activation of TRPV1 by endogenous anandamide has been reported. Ananda- mide, endogenously produced in the inflamed ileum of rats treated with toxin A, was shown to cause TRPV1-depend- ent ileitis [68]. This finding strengthens the hypothesis that anandamide behaves as an endovanilloid particularly under some pathological conditions, such as inflammation. With respect to the central nervous system, it is not known whether endogenously formed anandamide activates TRPV1 under normal physiological conditions. Exogenous anandamide induces, in hippocampal slices, a TRPV1- mediated enhancement of paired-pulse depression, which is a form of short-term synaptic plasticity [73]. Tonically activated TRPV1 receptors have been found in the substantia nigra compacta. While the mechanism of activa- tion has not been elucidated, this suggests that TRPV1 might be involved in the control of movement [74]. Interestingly, the anandamide uptake inhibitor and TRPV1 agonist, AM404 [N-(4-hydroxyphenyl)-arachidonyl- Ó FEBS 2004 Endovanilloids (Eur. J. Biochem. 271) 1831 ethanolamine], and capsaicin could attenuate, via direct activation of TRPV1, motor disturbances by restoring GABA and dopamine transmission in an animal model for Huntington’s disease [75,76]. However, capsazepine alone did not affect motor disturbances, arguing against a tonic activation of TRPV1 receptors in this animal model [76]. Finally, hippocampal anandamide has been shown to be up-regulated during kainate-induced seizures in mice [77], while capsazepine was shown to reduce neuronal damage in another animal model of excitotoxicity [78]. This suggests that anandamide-mediated activation of TRPV1 might contribute to neurotoxicity and neurodegeneration under conditions of excitotoxicity [79]. Conclusion and perspectives At the moment, three classes of putative endogenous ligands for TRPV1 have been identified, i.e. N-arachidonoyldop- amine, lipoxygenase products of AA and anandamide, thereby providing a rationale for the presence of this protein outside the peripheral efferents of sensory neurons [5]. Although much progress has been made towards their characterization as endovanilloids, it is still unclear whether any of these ligands is indeed responsible of TRPV1- mediated physiological and pathological effects in and outside the sensory nervous system. To clarify this issue, it will be necessary to identify the physiological processes in which TRPV1 is participating, which can then lead to the characterization of its endogenous activators. Novel endo- vanilloids might also be discovered in this way. Conversely, knowledge about the stimulus-induced formation of any of the three classes of the endogenous ligands can lead to the identification of TRPV1-mediated physiological processes. By looking at the biosynthetic routes of the putative endovanilloids, it can be suggested that each of the ligands is formed in a spatially and temporally different manner to selectively gate TRPV1 with different potencies and effica- cies. For example, while constitutive activity of lipoxygen- ases responsible for the formation of some endovanilloids is low under normal physiological conditions – especially in the central nervous system – its activity and expression are upregulated under pathological conditions, such as inflam- mation, asthma and neurodegeneration. At the moment, the biosynthetic pathway of N-arachidonoyldopamine and its regulation still need to be clarified. Although anandamide biosynthesis is also significantly upregulated during patho- logical conditions, it is important to notice that normal neuronal activity leads to production of anandamide, thereby making anandamide a likely candidate to be an endovanilloid in the central nervous system, also under physiological conditions. Molecular probes directed at manipulating the biosynthesis and metabolism of putative endovanilloids and genetically engineered mice lacking functional genes for fatty acid amide hydrolase, 12- or 15-lipoxygenase, N-acyl-phosphatidylethanolamine-select- ive PLD and TRPV1, will be highly informative while dissecting the physiological processes in which endovanil- loids are active. Finally, the biosynthetic and metabolic proteins of endovanilloids might serve as valuable targets for drug development for the increasing number of diseases associated with abnormal TRPV1 signaling, such as neuro- pathic pain, cough and urinary incontinence [2,71]. Acknowledgements The authors’ research on this subject is funded by a research grant from the Volkswagen Stiftung. References 1. Caterina, M., Schumacher, M., Tominaga, M., Rosen, T., Levine, J. & Julius, D. (1997) The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824. 2. Szallasi, A. & Blumberg, P.M. (1999) Vanilloid (Capsaicin) receptors and mechanisms. Pharmacol. Rev. 51, 159–212. 3. Caterina,M.,Leffler,A.,Malmberg,A.,Martin,W.,Trafton,J., Petersen-Zeitz, K., Koltzenburg, M., Kasbaum, A. & Julius, D. (2000) Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288, 306–313. 4. Davis, J.B., Gray, J., Gunthorpe, M.J., Hatcher, J.P., Davey, P.T., Overend, P., Harries, M.H., Latcham, J., Clapham, C., Atkinson, K., et al. (2000) Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405, 183–187. 5. Caterina, M.J. (2003) Vanilloid receptors take a TRP beyond the sensory afferent. Pain 105, 5–9. 6. Mezey, E., Toth, Z.E., Cortright, D.N., Arzubi, M.K., Krause, J.E., Elde, R., Guo, A., Blumberg, P.M. & Szallasi, A. (2000) Distribution of mRNA for vanilloid receptor subtype 1 (VR1, and VR1-like inmmunoreactivity, in the central nervous system of the rat and human. Proc.NatlAcad.Sci.USA97, 3655–3660. 7. Roberts, J.C., Davis, J.B. & Benham, C.D. (2004) [ 3 H]-Resini- feratoxin autoradiography in the CNS of wild-type and TRPV1 null mice defines TRPV1 (VR-1) protein distribution. Brain Res. 995, 176–183. 8. De Petrocellis, L., Bisogno, T., Maccarrone, M., Davis, J.B., Finazzi-Agro, A. & Di Marzo, V. (2001) The activity of ananda- mide at vanilloid VR1 receptors requires facilitated transport across the cell membrane and is limited by intracellular metabo- lism. J. Biol. Chem. 276, 12856–12863. 9. Jordt, S.E.J. (2002) Molecular basis for species-specific sensitivity to ÔhotÕ chili peppers. Cell 108, 421–430. 10. Huang, S.M., Bisogno, T., Trevisani, M., Al-Hayani, A., De Petrocellis, L., Fezza, F., Tognetto, M., Petros, T.J., Krey, J.F., Chu, C.J., et al. (2002) An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc. Natl Acad. Sci. USA. 99, 8400–8405. 11. Chu, C.J., Huang, S.M., De Petrocellis, L., Bisogno, T., Ewing, S.A., Miller, J.D., Zipkin, R.E., Daddario, N., Appendino, G., Di Marzo, V. & Walker, J.M. (2003) N-oleoyldopamine: a novel endogenous capsaicin-like lipid that produces hyperalgesia. J. Biol. Chem. 278, 13633–13639. 12. Hillard, C. & Jarrahian, A. (2003) Cellular accumulation of anandamide: consensus and controversy. Br.J.Pharmacol.140, 802–808. 13. Toth, A., Kedei, N., Wang, Y. & Blumberg, P.M. (2003) Arachidonyl dopamine as a ligand for the vanilloid receptor VR1 of the rat. Life Sci. 73, 487–498. 14. Di Marzo, V., De Petrocellis, L., Fezza, F., Ligresti, A. & Bisogno, T. (2002) Anandamide receptors. Prostaglandins Leukot. Essent. Fatty Acids 66, 377–391. 15. Harrison, S., De Petrocellis, L., Trevisani, M., Benvenuti, F., Bifulco, M., Geppetti, P. & Di Marzo, V. (2003) Capsaicin-like effects or N-arachidonoyl-dopamine in the isolated guinea pig bronchi and urinary bladder. Eur. J. Pharmcol. 475, 107–114. 16. Hwang, S.W., Cho, H., Kwak, J., Lee, S.Y., Kang, C.J., Jung, J., Cho, S., Min, K.H., Suh, Y.G., Kim, D. & Oh, U. (2000) Direct activation of capsaicin receptors by products of lipoxygenases: endogenous capsaicin-like substances. Proc. Natl Acad. Sci. USA. 97, 6155–6160. 1832 M. van der Stelt and V. Di Marzo (Eur. J. Biochem. 271) Ó FEBS 2004 17. Funk, C.D. (2001) Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875. 18. Kuhn, H., Walther, M. & Kuban, R.J. (2002) Mammalian arachidonate 15-lipoxygenases. Structure, function and bio- logical implications. Prostaglandins Other Lipid Mediat. 68–69, 263–290. 19. Yoshimoto, T. & Takahashi, Y. (2002) Arachidonate 12-lipoxy- genases. Prostaglandins Other Lipid Mediat. 68–69, 245–262. 20. Nishiyama, M., Okamoto, H., Watanabe, T., Hori, T., Hada, T., Ueda, N., Yamamoto, S., Tsukamoto, H., Watanabe, K. & Kirino, T. (1992) Localization of arachidonate 12-lipoxygenase in canine brain tissues. J. Neurochem. 58, 1395–1400. 21. Nishiyama, M., Watanabe, T., Ueda, N., Tsukamoto, H. & Watanabe, K. (1993) Arachidonate 12-lipoxygenase is localized in neurons, glial cells, and endothelial cells of the canine brain. J. Histochem. Cytochem. 41, 111–117. 22. Shin, J., Cho, H., Hwang, S.W., Jung, J., Shin, C.Y., Lee, S.Y., Kim, S.H., Lee, M.G., Choi, Y.H., Kim, J., et al. (2002) Bra- dykinin-12-lipoxygenase-VR1 signaling pathway for inflamma- tory hyperalgesia. Proc. Natl Acad. Sci. USA 99, 10150–10155. 23. Cravatt, B.F., Giang, D.K., Mayfield, S.P., Boger, D.L., Lerner, R.A. & Gilula, N.B. (1996) Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature 384, 83–87. 24. Hampson, A.J., Hill, W.A., Zan-Phillips, M., Makriyannis, A., Leung, E., Eglen, R.M. & Bornheim, L.M. (1995) Anandamide hydroxylation by brain lipoxygenase: metabolite structures and potencies at the cannabinoid receptor. Biochim. Biophys. Acta 1259, 173–179. 25. Edgemond, W.S., Hillard, C.J., Falck, J.R., Kearn, C.S. & Campbell, W.B. (1998) Human platelets and polymorphonuclear leukocytes synthesize oxygenated derivatives of arachidonyletha- nolamide (anandamide): their affinities for cannabinoid receptors and pathways of inactivation. Mol. Pharmacol. 54, 180–188. 26. Ueda, N., Yamamoto, K., Yamamoto, S., Tokunaga, T., Shirakawa, E., Shinkai, H., Ogawa, M., Sato, T., Kudo, I., Inoue, K. et al. (1995) Lipoxygenase-catalyzed oxygenation of arachi- donylethanolamide, a cannabinoid receptor agonist. Biochim. Biophys. Acta 1254, 127–134. 27. van der Stelt, M., van Kuik, J.A., Bari, M., van Zadelhoff, G., Leeflang, B.R., Veldink, G.A., Finazzi-Agro, A., Vliegenthart, J.F. & Maccarrone, M. (2002) Oxygenated metabolites of ana- ndamide and 2-arachidonoylglycerol: conformational analysis and interaction with cannabinoid receptors, membrane transporter, and fatty acid amide hydrolase. J. Med. Chem. 45, 3709–3720. 28. Maccarrone, M., van der Stelt, M., Rossi, A., Veldink, G.A., Vliegenthart, J.F. & Finazzi Agro, A. (1998) Anandamide hydrolysis by human cells in culture and brain. J. Biol. Chem. 273, 32332–32339. 29. Craib, S.J., Ellington, H.C., Pertwee, R.G. & Ross, R.A. (2001) A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig bronchus. Br. J. Pharmacol. 134, 30–37. 30. Kagaya, M., Lamb, J., Robbins, J., Page, C.P. & Spina, D. (2002) Characterization of the anandamide induced depolarization of guinea-pig isolated vagus nerve. Br. J. Pharmacol. 137, 39–48. 31. De Petrocellis, L., Harrison, S., Bisogno, T., Tognetto, M., Brandi, I., Smith, G.D., Creminon, C., Davis, J.B., Geppetti, P. & Di Marzo, V. (2001) The vanilloid receptor (VR1) -mediated effects of anandamide are potently enhanced by the cAMP-de- pendent protein kinase. J. Neurochem. 77, 1660–1663. 32. McLean, P.G., Aston, D., Sarkar, D. & Ahluwalia, A. (2002) Protease-activated receptor-2 activation causes EDHF-like cor- onary vasodilation: selective preservation in ischemia/reperfusion injury: involvement of lipoxygenase products, VR1 receptors, and C-fibers. Circ. Res. 90, 465–472. 33. Hwang, S.W. & Oh, U. (2002) Hot channels in airways: phar- macology of the vanilloid receptor. Curr. Opin. Pharmacol. 2, 235–242. 34. Kollarik, M. & Undem, B. (2003) Activation of broncho- pulmonary vagal afferent nerves with bradykinin, acid and vanilloid receptor agonists in wildtype and TRPV1–/– mice. J. Physiol., 555, 115–123. 35. Devane, W.A., Hanus, L., Breuer, A., Pertwee, R.G., Stevenson, L.A., Griffin, G., Gibson, D., Mandelbaum, A., Etinger, A. & Mechoulam, R. (1992) Isolation and structure of a brain con- stituent that binds to the cannabinoid receptor. Science 258, 1946– 1949. 36. Di Marzo, V., Melck, D., Bisogno, T. & De Petrocellis, L. (1998) Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 21, 521–528. 37. Schmid, H.H. (2000) Pathways and mechanisms of N-acyletha- nolamine biosynthesis: can anandamide be generated selectively? Chem. Phys. Lipids 108, 71–87. 38. Zygmunt, P.M., Petersson, J., Andersson, D.A., Chuang, H., Sorgard, M., Di Marzo, V., Julius, D. & Hogestatt, E.D. (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 400, 452–457. 39. Smart, D., Gunthorpe, M.J., Jerman, J.C., Nasir, S., Gray, J., Muir, A.I., Chambers, J.K., Randall, A.D. & Davis, J.B. (2000) The endogenous lipid anandamide is a full agonist at the human vanilloid receptor (hVR1). Br. J. Pharmacol. 129, 227–230. 40. Di Marzo, V., Fontana, A., Cadas, H., Schinelli, S., Cimino, G., Schwartz, J.C. & Piomelli, D. (1994) Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature 372, 686–691. 41. Okamoto, Y., Morishita, J., Tsuboi, K., Tonai, T. & Ueda, N. (2004) Molecular characterization of a phospholipase D generat- ing anandamide and its congeners. J. Biol. Chem. 279, 5298–5305. 42. Ahluwalia, J.Y.M., Urban, L., Bevan, S. & Nagy, I. (2003) Acti- vation of capsaicin-sensitive primary sensory neurones induces anandamide production and release. J. Neurochem. 84, 585–591. 43. Van der Stelt, M. & Di Marzo, V. (2004) Metabolic fate of en- docannabinoids. Current Neuropharm. 2, 37–48. 44. Hillard, C.J., Edgemond, W.S., Jarrahian, A. & Campbell, W.B. (1997) Accumulation of N-arachidonoylethanolamine (ananda- mide) into cerebellar granule cells occurs via facilitated diffusion. J. Neurochem. 69, 631–638. 45. Beltramo, M., Stella, N., Calignano, A., Lin, S.Y., Makriyannis, A. & Piomelli, D. (1997) Functional role of high-affinity ana- ndamide transport, as revealed by selective inhibition. Science 277, 1094–1097. 46. De Petrocellis, L., Bisogno, T., Davis, J.B., Pertwee, R.G. & Di Marzo, V. (2000) Overlap between the ligand recognition proper- ties of the anandamide transporter and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS Lett. 483, 52–56. 47. Lopez-Rodriguez, M.L., Viso, A., Ortega-Gutierrez, S., Fowler, C.J., Tiger, G., de Lago, E., Fernandez-Ruiz, J. & Ramos, J.A. (2003) Design, synthesis, and biological evaluation of new inhibitors of the endocannabinoid uptake: comparison with effects on fatty acid amidohydrolase. J. Med. Chem. 46, 1512– 1522. 48. Ortar, G.L.A., De Petrocellis, L., Morera, E. & Di Marzo, V. (2003) Novel selective and metabolically stable inhibitors of ana- ndamide cellular uptake. Biochem. Pharmacol. 65, 1473–1481. 49. Deutsch, D.G., Ueda, N. & Yamamoto, S. (2002) The fatty acid amide hydrolase (FAAH). Prostaglandins Leukot. Essent. Fatty Acids 66, 201–210. 50. Kozak, K.R. & Marnett, L.J. (2002) Oxidative metabolism of endocannabinoids. Prostaglandins Leukot. Essent. Fatty Acids 66, 211–220. Ó FEBS 2004 Endovanilloids (Eur. J. Biochem. 271) 1833 51. Cravatt, B.F., Demarest, K., Patricelli, M.P., Bracey, M.H., Giang, D.K., Martin, B.R. & Lichtman, A.H. (2001) Super- sensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc. Natl Acad. Sci. USA 98, 9371–9376. 52. Egertova, M., Giang, D.K., Cravatt, B.F. & Elphick, M.R. (1998) A new perspective on cannabinoid signalling: complementary localization of fatty acid amide hydrolase and the CB1 receptor in rat brain. Proc. R. Soc. Lond. B Biol Sci. 265, 2081–2085. 53. Ross, R.A. (2003) Anandamide and vanilloid TRPV1 receptors. Br.J.Pharmacol.140, 790–801. 54. Ross, R.A., Coutts, A.A., McFarlane, S.M., Anavi-Goffer, S., Irving, A.J., Pertwee, R.G., MacEwan, D.J. & Scott, R.H. (2001) Actions of cannabinoid receptor ligands on rat cultured sensory neurones: implications for antinociception. Neuropharmacology 40, 221–232. 55. De Petrocellis, L., Davis, J.B. & Di Marzo, V. (2001) Palmitoyl- ethanolamide enhances anandamide stimulation of human vanilloid VR1 receptors. FEBS Lett. 506, 253–256. 56. Smart, D., Jerman, J.C., Gunthorpe, M.J., Brough, S.J., Ranson, J., Cairns, W., Hayes, P.D., Randall, A.D. & Davis, J.B. (2001) Characterisation using FLIPR of human vanilloid VR1 receptor pharmacology. Eur. J. Pharmacol. 417, 51–58. 57. Andersson, D.A., Adner, M., Hogestatt, E.D. & Zygmunt, P.M. (2002) Mechanisms underlying tissue selectivity of anandamide and other vanilloid receptor agonists. Mol. Pharmacol. 62, 705–713. 58. Ralevic, V., Kendall, D.A., Jerman, J.C., Middlemiss, D.N. & Smart, D. (2001) Cannabinoid activation of recombinant and endogenous vanilloid receptors. Eur. J. Pharmacol. 424, 211–219. 59. Szolcsanyi, J. (2000) Are cannabinoids endogenous ligands for the VR1 capsaicin receptor? Trends Pharmacol Sci. 21, 41–42. 60. Di Marzo, V., Blumberg, P.M. & Szallasi, A. (2002) Endovanilloid signaling in pain. Curr. Opin. Neurobiol. 12, 372–379. 61. Trevisani, M., Smart, D., Gunthorpe, M.J., Tognetto, M., Barbieri, M., Campi, B., Amadesi, S., Gray, J., Jerman, J.C., Brough, et al. (2002) Ethanol elicits and potentiates noci- ceptor responses via the vanilloid receptor-1. Nat. Neurosci. 5, 546–551. 62. Chuang, H.H., Prescott, E.D., Kong, H., Shields, S., Jordt, S.E., Basbaum, A.I., Chao, M.V. & Julius, D. (2001) Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5),P2-mediated inhibition. Nature 411, 957–962. 63. Premkumar, L.S. & Ahern, G.P. (2000) Induction of vanilloid receptor channel activity by protein kinase C. Nature 408, 985–990. 64. Tominaga, M., Wada, M. & Masu, M. (2001) Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATP-evoked pain and hyperalgesia. Proc. Natl Acad. Sci.USA 98, 6951–6956. 65. Bonnington, J. & McNaughton, P. (2003) Signalling pathways involved in the sensitisation of mouse nociceptive neurones by nerve growth factor. J. Physiol. 551, 433–446. 66. Ahern, G. & Premkumar, L. (2002) Voltage-dependent priming of rat vanilloid receptor: effects of agonist and protein kinase C activation. J. Physiol. 545, 441–451. 67. Numazaki, M., Tominaga, T., Takeuch, K., Murayama, N., Toyooka, H. & Tominaga, M. (2003) Structural determinant of TRPV1 desensitization interacts with calmodulin. Proc. Natl Acad. Sci. USA 100, 8002–8006. 68. McVey, D., Schmid, P., Schmid, H. & Vigna, S. (2003) Endocannabinoids induce ileitis in rats via the capsaicin receptor (VR1). J. Pharmacol. Exp. Ther. 304, 713–722. 69. Smart, D., Jonsson, K.O., Vandevoorde, S., Lambert, D.M. & Fowler, C.J. (2002) ÔEntourageÕ effects of N-acyl ethanolamines at human vanilloid receptors. Comparison of effects upon ananda- mide-induced vanilloid receptor activation and upon anandamide metabolism. Br. J. Pharmacol. 136, 452–458. 70. Ahern, G. (2003) Activation of TRPV1 by the satiety factor oleoylethanolamide. J. Biol. Chem. 278, 30429–30434. 71. Szallasi, A. (2002) Vanilloid (capsaicin) receptors in health and disease. Am.J.Clin.Pathol.118, 110–121. 72. Hogestatt, E.D. & Zygmunt, P.M. (2002) Cardiovascular phar- macology of anandamide. Prostaglandins Leukot. Essent. Fatty Acids 66, 343–351. 73. Al-Hayani, A., Wease, K.N., Ross, R.A., Pertwee, R.G. & Davies, S.N. (2001) The endogenous cannabinoid anandamide activates vanilloid receptors in the rat hippocampal slice. Neuropharma- cology 41, 1000–1005. 74. Marinelli, S., Di Marzo, V., Berretta, N., Matias, I., Maccarrone, M., Bernardi, G. & Mercuri, N.B. (2003) Presynaptic facilitation of glutamatergic synapses to dopaminergic neurons of the rat substantia nigra by endogenous stimulation of vanilloid receptors. J. Neurosci. 23, 3136–3144. 75. Lastres-Becker, I., Hansen, H.H., Berrendero, F., De Miguel, R., Perez-Rosado, A., Manzanares, J., Ramos, J.A. & Fernandez- Ruiz, J. (2002) Alleviation of motor hyperactivity and neuro- chemical deficits by endocannabinoid uptake inhibition in a rat model of Huntington’s disease. Synapse 44, 23–35. 76. Lastres-Becker, I., de Miguel, R., De Petrocellis, L., Makriyannis, A., Di Marzo, V. & Fernandez-Ruiz, J. (2003) Compounds acting at the endocannabinoid and/or endovanilloid systems reduce hyperkinesia in a rat model of Huntington’s disease, J. Neuro- chem. 84, 1097–1109. 77. Marsicano, G., Goodenough, S., Monory, K., Hermann, H., Eder, M., Cannich, A., Azad, S.C., Cascio, M.G., Gutierrez, S.O., van der Stelt, M. et al. (2003) CB1 cannabinoid receptors and on- demand defense against excitotoxicity. Science 302, 84–88. 78. Veldhuis, W.B., Van Der Stelt, M., Wadman, M.W., Van Zadelhoff, G., Maccarrone, M., Fezza, F., Veldink, G.A., Vliegenthart, J.F., Bar, P.R., Nicolay, K. & Di Marzo, V. (2003) Neuroprotection by the endogenous cannabinoid anandamide and arvanil against in vivo excitotoxicity in the rat: role of vanilloid receptors and lipoxygenases. J. Neurosci. 23, 4127–4133. 79. van der Stelt, M., Veldhuis, W.B., Maccarrone, M., Bar, P.R., Nicolay, K., Veldink, G.A., Di Marzo, V. & Vliegenthart, J.F. (2002) Acute neuronal injury, excitotoxicity, and the endo- cannabinoid system. Mol. Neurobiol. 26, 317–346. 80. Ahluwalia, J., Urban, L., Bevan, S. & Nagy, I. (2003) Ananda- mide regulates neuropeptide release from capsaicin-sensitive pri- mary sensory neurons by activating both the cannabinoid 1 receptor and the vanilloid receptor 1 in vitro. Eur. J. Neurosci. 7, 2611–2618. 1834 M. van der Stelt and V. Di Marzo (Eur. J. Biochem. 271) Ó FEBS 2004 . MINIREVIEW Endovanilloids Putative endogenous ligands of transient receptor potential vanilloid 1 channels Mario van der Stelt and. Ricerche, Pozzuoli, Italy Endovanilloids are defined as endogenous ligands of the transient receptor potential vanilloid type 1 (TRPV1) protein, a nonselective

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